79
4.10 CORRELATES AND PREDICTORS OF LEFT VENTRICULAR SYSTOLIC
80
TABLE 15: Correlates of systolic function (EF) in Subjects
VARIABLES
EF CORRELATION CO-EFFICIENT
p-Value
Gestational Age (years) 0.340 0.001*
Height (m) 0.218 0.028*
Weight(Kg) 0.276 0.005*
BMI 0.224 0.024*
BSA 0.295 0.003*
SBP(mmHg) 0.206 0.039*
DBP (mmHg) 0.232 0.020*
Heart rate (bpm) 0.321 0.001*
MAP (mmHg) 0.242 0.015*
SV (ml) 0.266 0.013*
CO (L/min) 0.445 <0.001*
SVR (dyn x sec/cm5) -0.312 0.005*
BMI= body mass index, BSA= body surface area, SBP= systolic blood pressure, DBP=
diastolic blood pressure, MAP= mean arterial pressure. SV= stroke volume, CO= cardiac output, SVR= systemic vascular resistance. *P is significant at <0.05
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TABLE 16: Predictors of Systolic function (Ejection Fraction) in subjects
MODEL VARIABLE R R2 p- value
1 CO (L/min) 0.435 0.190 <0.001*
2 DBP 0.512 0.262 <0.001*
3 Gestational age 0.551 0.304 <0.001*
a. Predictors: (Constant), Cardiac output
b. Predictors: (Constant), Cardiac output, Diastolic Blood Pressure
c. Predictors: (Constant), Cardiac output, Diastolic Blood Pressure, Gestational Age
*P is significant at <0.05
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CORRELATES AND PREDICTORS OF LEFT VENTRICULAR DIASTOLIC FUNCTION AMONG ALL SUBJECTS
Table 17 shows that the mitral E/A, an index of diastolic function correlated positively with Pulse Pressure and negatively with Age, Height, Heart rate, Total Cholesterol, and Triglyceride. A stepwise multiple regression was conducted to evaluate whether all these correlates were necessary to predict Mitral E/A ratio. At step 1 of the analysis, Pulse pressure entered into the regression equation and was significantly related to Mitral E/A ratio F (1,86)
= 11.220, p= 0.001. The multiple correlation coefficient was .340, indicating approximately 11.6% of the variance of the Mitral E/A ratio could be accounted for by pulse pressure.
Height entered into the equation at step 2 of the analysis F (2,85) = 9.705, p <0.001, Heart rate at step 3 F (3, 84) = 8.509, p< and age at step 4 F (4,83) = 7.796, p <0.001 as shown in Table 18. Thus the regression equation for predicting mitral E/A ratio was:
Predicted Mitral E/A ratio = 3.093 + 0.009(Pulse Pressure) – 0.008(Height) – 0.004(Heart rate) – 0.010(Age).
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TABLE 17: Correlates of Diastolic function (Mitral E/A ratio) in subjects
VARIABLES MITRAL E/A
CORRELATION CO-EFFICIENT
p-Value
Age (years) -0.245 0.016*
Height (m) -0.212 0.037*
Heart rate (bpm) -0.255 0.012*
Pulse Pressure ((mmHg)) 0.297 0.003*
Total Cholesterol (mmol/L) -0.201 0.049*
Triglyceride (mmol/L) -0.214 0.035*
*P is significant at <0.05
84
TABLE 18: Predictors of Diastolic function (Mitral E/A ratio) in Subjects
MODEL VARIABLE R R2 p- value
1 Pulse Pressure 0.340 0.116 0.001*
2 Height 0.432 0.189 <0.001*
3 Heart Rate 0.484 0.234 <0.001*
4 Age 0.523 0.274 <0.001*
a. Predictors: (Constant), Pulse pressure
b. Predictors: (Constant), Pulse pressure, Height
c. Predictors: (Constant), Pulse pressure, Height, Heart Rate d. Predictors: (Constant), Pulse pressure, Height, Heart Rate, Age
*P is significant at <0.05
85
CORRELATES AND PREDICTORS OF CARDIAC OUTPUT AMONG SUBJECTS
The cardiac output correlated positively with Ejection fraction, Gestational age, Height, Weight, BMI, stroke volume and left ventricular mass but negatively with systemic vascular resistance as shown in Table 19. A stepwise multiple regression was conducted to evaluate whether all these correlates were necessary to predict Cardiac output. At step 1 of the analysis, systemic vascular resistance entered into the regression equation and was significantly related to cardiac output F (1,73) = 226.6, p <0.001. The multiple correlation coefficient was .870, indicating approximately 84.4% of the variance of the cardiac output could be accounted for by systemic vascular resistance. Stroke volume entered into the equation at step 2 of the analysis F (2,72) = 194.5, p <0.001 and Ejection fraction at step 3 F (3,71) = 147.8, p <0.001 as shown in Table 20. Thus the regression equation for predicting cardiac output was:
Predicted Cardiac output = 4.634 – 0.003(SVR) + 0.44 (SV) + 0.023 (EF)
86 TABLE 19: Correlates of Cardiac output in subjects
VARIABLES EF CORRELATION
CO-EFFICIENT
p-Value
Ejection fraction (%) 0.445 <0.001*
Gestational age (years) 0.442 <0.001*
Height (m) 0.244 0.026*
Weight (kg) 0.432 <0.001*
BMI 0.382 <0.001*
SV (ml) 0.861 <0.001*
LVM (g) 0.291 0.008*
SVR (dyn x sec/cm5) -0.873 <0.001*
BMI= body mass index, SV= stroke volume, LVM= left ventricular mass, SVR= systemic vascular resistance, *P is significant at <0.05
87 TABLE 20: Predictors of Cardiac output in subjects
MODEL VARIABLE R R2 p- value
1 SVR 0.870 0.757 <0.001*
2 Stroke Volume 0.919 0.844 <0.001*
3 Ejection Fraction 0.929 0.862 0.018*
a. Predictors: (Constant), SVR
b. Predictors: (Constant), SVR, Stroke Volume
c. Predictors: (Constant), SVR, Stroke Volume, Ejection fraction
*P is significant at <0.05
88 4.11 Lipid profile
All the parameters in the lipid profile were higher in pregnant women but in different pattern.
The total cholesterol (T chol), low density lipoprotein cholesterol (LDL-c) and triglyceride increase progressively from first to the third trimester while the high density lipoprotein cholesterol (HDL-c) demonstrated an initial increase in the first trimester with a fall towards the control in the second trimester before a final rise in the third trimester. The mean total cholesterol (6.26 ± 1.44 vs. 4.44 ± 1.01 mmol/L, P=0.001), LDL-c (4.54 ± 1.40 vs. 3.21 ± 0.87 mmol/L, p=0.010) and Triglycerides (1.26 ± 0.47 vs. 0.52 ± 0.27 mmol/L, p<0.001) are significantly higher than that of the control while the mean HDL-c (1.17 ± 0.37 vs. 1.02 ± 0.17mmol/L, p= 0.065) is not significantly higher as shown in Table 21. Also the increase in the total cholesterol and LDL-c are particularly higher in the third trimester and values are more than the reference range of normal individual. The increase in the triglycerides is more in the first trimester with only modest increases in the second and third trimester with all the values within normal limit as shown in Table 22. Additionally, the triglyceride in the controls demonstrated a value close to the lower limit of normal.
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TABLE 21: Lipid profile pattern of subjects and control
Variables
Subjects (N=96) Mean ± SD
Controls
(N=100) Mean ± SD
p- value
T chol (mmol/L) 6.26 ± 1.44 4.44 ± 1.01 0.001*
HDL-c (mmol/L) 1.17 ± 0.37 1.02 ± 0.17 0.065
LDL-c (mmol/L) 4.54 ± 1.40 3.21 ± 0.87 0.010*
Trig (mmol/L) 1.26 ± 0.47 0.52 ± 0.27 <0.001*
AIP 6.06 ± 3.58 4.37 ± 1.07 <0.001*
Key: SD= standard deviation, T chol= total cholesterol, HDL-c= High density lipoprotein, LDL-c = low density lipoprotein. Trig= Triglyceride. T1= first trimester, T2= second trimester, T3= third trimester. * Statistical significance between all pregnant women and controls.
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TABLE 22: ANOVA table comparing the Lipid profile parameters among subjects in each trimester and Controls
Variables
T1 (N=24) Mean ±
SD
T2 (N=39) Mean ±
SD
T3 (N=33) Mean ±
SD
Controls (N=100) Mean ± SD
p- value
Post-hoc test§
T chol (mmol/L)
5.21 ± 1.08 5.92 ± 1.24 7.14 ± 1.26 4.44 ± 1.01 <0.001 T2 > C T3 > C T3 > T1 T3 > T2 HDL-c
(mmol/L)
1.26 ± 0.23 1.05 ± 0.44 1.25 ± 0.31 1.02 ± 0.17 0.047
LDL-c (mmol/L)
3.58 ± 1.00 4.28 ± 1.30 5.31 ± 1.25 3.21 ± 0.87 <0.001 T3 > C T3 > T1 T3 > T2 Trig
(mmol/L)
1.13 ± 0.32 1.29 ± 0.56 1.31 ± 0.44 0.52 ± 0.27 <0.001 T1 > C T2 > C T3 > C AIP 4.48 ± 1.21 6.65 ± 3.17 6.25 ± 3.17 4.37 ± 1.07 0.07
Key: SD= standard deviation, T chol= total cholesterol, HDL-c= High density lipoprotein, LDL-c = low density lipoprotein. Trig= Triglyceride. T1= first trimester, T2= second trimester, T3= third trimester. * Statistical significance among pregnant women in all trimesters and controls. § Post hoc test with Bonferroni’s correction
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FIGURE 6: Bar chart showing the variation in the lipid profile in various trimesters of pregnancy. 0= controls, 1= subjects in first trimester, 2= subjects in second trimester, 3=
subjects in second trimester.
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CHAPTER FIVE DISCUSSION 5.0 Demographics and anthropometric measurement
There are fewer women in the first trimester because preganat women don’t usually come for antenatal care antenatal care early enough. The mean age was similar between the pregnant women and controls. The age at first pregnancy was higher in the controls possibly because more had tertiary education which was likely to have delayed the age at marriage and child delivery. More women in the control group were nulliparous because most of them were undergraduate students of LAUTECH. The monthly income was similar in both pregnant women and controls likely reflecting the small income in pregnant women majority of whom are married and working class. Their level of education and indeed their occupation which was petty trading may account for this.
The mean weight and body mass index (BMI) of pregnant women were significantly higher than those of the controls. This is expected due to the additional impact of the increase in the mass of the uterus, the fetus, amniotic fluid and placenta in the pregnant women.
The decrease in the systolic, diastolic and the mean arterial pressures observed in the pregnant women was due to a decline in the systemic vascular resistance associated with pregnancy as shown in this study. The decline in the systemic vascular resistance has been adduced to enhanced vasodilatation as a result of decreased vascular responsiveness to vasopressors such as angiotensin II and norepinephrine 38-40, increased endothelial prostacyclin 41, enhanced nitric oxide production 42, reduced aortic stiffness 43and increased progesterone.
93 5.1 Heamodynamics
Compared with the age matched control, this study demonstrated a 39% increase in cardiac output which represented a progressive increase from first trimester through to the third trimester. The individual contribution of stroke volume and heart rate were 23% and 16%
respectively
This study generally agrees with previous studies, both longitudinal and cross sectional in pregnant women on increase in cardiac output contributed variably by increase in stroke volume and heart rate. The heart rate increase during pregnancy generally range between 10 and 30%37,102,103 while stroke volume range between 10 and 50%37,48,103,104 resulting in total increase in cardiac output of 30 to 50 %17
The pattern of increase in the cardiac output in this study is such that it rises progressively from the first trimester through the second trimester to peak in the third trimester. This is similar to longitudinal studies by Desai et al. 79 and Mabie et al. 105. Other studies however showed a peak increase in the second trimester which is either maintained in the third trimester or decreased in the third trimester.
These differences stem from a lot of factors which include the type of study design, method of evaluation of the heamodynamics, maternal position during examination and variations in the timing of data collection.
The variations in the peak increase in cardiac output which occurred either in second trimester or third trimester may be due to difference study design. In the meta-analysis of cross-sectional studies, van Oppen et al 6363 showed a trend to a lower cardiac output in the third trimester compared with the second, the authors observed large ranges in cardiac output among the different studies that did not allow for any firm conclusions. However, in the 6
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longitudinal studies evaluated, van Oppen et al.63 found that cardiac output between the second and third trimesters plateaued, decreased, or increased. Of these, the 4 studies with comparable techniques still showed striking differences in the course of cardiac output in the third trimester, with Duvekot et al.48 showing a decrease of 11.5%, no change by Robson et al.37 and increases of 9.3% by Mabie et al.105 and 16.4% by Thomsen et al.106 Although design differences and measurement techniques among studies can explain some of the reported differences in maternal hemodynamics in normal pregnancy, most researchers concur that patient factors rather than measurement error are largely responsible for discrepancies in reported studies.
Easterling et al. 107 established a fall in mean cardiac output from 34 weeks of gestation until the last measurement before delivery. However, the performance of individual subjects between 34 weeks and delivery varied. 29% of the subjects had a fall in cardiac output while 9% had a rise in cardiac output. Similar variation was observed by Caton and Banner 107 in a Doppler echocardiographic study of 20 women with normal pregnancy which demonstrated a wide variation in individual subjects presented on a graph. Studies with other modalities of assessment of cardiac output also confirm this variation in cardiac output in the third trimester as Lee et al. 109 demonstrated in study of 5 pregnant women using the indicator dilution technique. While two of the five subjects showed a decrease between the second and third trimester, three showed an increase. Additionally, though there was a mean decrease in cardiac output from second to third trimester in a study of 50 pregnant women by van Oppen et al.110 using thoracic electric bioimpedance, up to 18% had an increase in cardiac output in the third trimester over the second. The general characteristics of those who showed increase or decrease were noted to be similar.
This discrepancy in the course of cardiac output in third trimester could be due to individual factors which uterine volume or weight, degree of paraventricular venous collateral
95
circulation, anatomy of the lumbar spine and position of the inferior vena cava along the spine.
Racial factors should not also be underestimated as some studies showed racial differences in the cardiac output. Hinderliter et al.111 have shown that LV wall thickness and TPR are higher, while resting cardiac output is lower, in healthy, adult black compared to white women. The finding in this study is consistent with those finding.
Also, as shown in this study and others112 parity correlates with cardiac output, so over representation of women with higher parity in the third trimester could also result in higher cardiac output relative to second trimester.
The discrepancies observed in cardiac output in the third trimester could also be as a result of so many factors including maternal position during examination as lying in the supine position is expected to decrease stroke volume by up to 5%113-115. This is due to the compression of the inferior vena cava by the uterus especially in the third trimester when the weight of the uterus is increased 64. Other factors include the race of the study population as well as the variation in the timing of data collection.
The third trimester is a variable period between the 27th and 40th week of pregnancy and studies differ in the timing especially cross sectional studies in which only one measurement is taken at any time within this period as the third trimester measurement.
The increase in the cardiac output in pregnancy has been attributed to the increase in preload brought about by the increase in both plasma11, 14 and blood cells17 as well as the decrease in afterload brought about by the decrease in the systemic vascular resistance as documented in this study and several others 17.
The decrease in systemic vascular resistance is the resultant effect of both vasodilation and the high flow, low-resistance circuit in multiple vascular beds37. The factors responsible for
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the vasodilatation are incompletely understood, but proposed mechanisms however include decreased vascular responsiveness to vasopressors such as angiotensin II and norepinephrine
38-40, increased endothelial prostacyclin 41, enhanced nitric oxide production 42, increased progesterone and reduced aortic stiffness 43.
5.2 Systolic Function
This study demonstrated an increase in left ventricular systolic function assessed by ejection fraction and fractional shortening in pregnancy which represents a progressive rise from first to third trimester. This finding is similar to the report of Clapp and Capeless116 who also found an increase in the ejection fraction up to the third trimester. However, unlike the Clapp and Capeless116 whose work found non-significant increase in the third trimester over the second, this study found a significant increase in the ejection fraction.
This increase in left ventricular systolic function measured by Teicholz formula could be as a result of Starling effect on left ventricular myofibres due to increase in preload from the increase in the blood volume associated with pregnancy. Other hormonal changes could also be responsible for possible change in left ventricular function in pregnancy.
In contrast to this study however, several other authors recorded either a decrease117, 118 in systolic function in pregnancy or no change in these parameters62, 119,120) during pregnancy.
All these studies assessed left ventricular systolic function using the Teicholz formula for the ejection fraction and there have been arguments over the appropriateness of this method of assessment in pregnancy. The assumption of this method that the left ventricle is an ellipsoid with its length double its width121, account for some of the weaknesses of the method and may be responsible for the discrepancies in the various reports of left ventricular systolic function in pregnancy.
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Left ventricular fibers are arranged predominantly longitudinally or obliquely in the subendocardium and subepicardium, but circumferentially in the intermediate layers. During early systole, the longitudinal and oblique fibers contract first, causing the cavity to become more spherical. The circumferential fibers then contract and are responsible for ejection. This accounts for why the circumferential fiber shortening has been the dominant basis for conventional analysis of LV systolic function during pregnancy by echocardiography with measurement of ventricular dimensions and hence the fractional shortening, ejection fraction and, mainly for research purposes, mean velocity of circumferential fiber shortening122.
However, the geometric assumptions made in the Teicholz formula of the left ventricles being an ellipsoid make it not reliable. Furthermore, the left ventricular ellipsoid assumption will also not be valid in cases of ventricular dilatation123 such as in pregnancy when there is an enormous increase in blood volume. Another shortcoming of the traditional indices is that the cursor derived systolic and diastolic dimensions of the LV from the parasternal view are not from the same part of the LV because of the movement of the heart along the long axis during the cardiac cycle. In pregnancy, calculation of the ejection fraction by two-dimensional echocardiography might also be limited because for the estimation of the ventricular systolic and diastolic dimensions good image quality is required for adequate tracing of the endocardial borders. This might be compromised, especially towards term, because the soft tissue edema and the change in position of the heart due to the pressure from the gravid uterus make adequate visualization of endocardial borders difficult. Other indices of LV systolic function are needed in pregnancy in addition to the traditional Teicholz method.
Some authors118 are now considering the use of left ventricular long-axis displacement as an index of systolic function which is independent of the changes in LV geometry
98 5.3 Diastolic Function
The diastolic function in this study was assessed by the transmitral flow pattern which showed an overall increase in both e-wave and a-wave velocities in pregnant women compared with non-pregnant controls.
The pattern of rise is such that there is an initial rise in both e- and a-wave peak velocities with subsequent decline in both to varying degrees relative to each other. In the first trimester, there is an increase in both and a-wave velocities with a higher increase in the e-wave velocity relative to the a-velocity resulting in a significant increase in the first trimester mitral E/A ratio. The second trimester demonstrated a similar pattern in both e- and a-wave velocities but with a higher a-wave velocity increase resulting in a lower mitral E/A ratio relative to the first trimester. The third trimester shows similar increase in e- and a- wave velocities over the non-pregnant control but with a higher increase in a wave velocity relative to the e-wave velocity resulting in a much lower mitral E/A ratio than the non-pregnant control. Therefore there is a progressive decline in the mitral E/A ratio throughout pregnancy.
The pattern of rise in the e-velocity relative to the a-velocity in the first trimester appears to be uniform in almost all the available studies37,80,118. However, there is a discrepancy over the pattern of change subsequently, with some studies showing no change in the e-velocity while others show a progressive increase in the e-velocity until term as in this study.
This study also showed a further rise in the second trimester followed by a fall in the third trimester similar to the finding of Bamfo et al.124 in a longitudinal study of 63 women who had serial echocardiography during the course of pregnancy. This also confirms the longitudinal observations by Valensise et al. 125 as well as a cross sectional study of Kametas et al.118 However, Mesa et al.126 also reported a progressive increase in the e-velocity while Mabie et al.105 demonstrated no change in the e-velocity after the initial rise in the first trimester.
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The initial rise in the maximum e-wave velocities in the first and second trimester may be accounted for by the increase in the venous return in the left atrium (preload) while their subsequent decrease in the third trimester to a fall in the preload in the last trimester.
A relative higher a-velocity may be explained by the rise in afterload in third trimester and the increase left ventricular compliance. The increase in the afterload is as a result of a rise in mean arterial pressure which is observed in the third trimester of pregnancy as shown in this study. The increase left ventricular compliance may be consequent upon increasing LVMi which is also demonstrated in this study and previous work