Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Cardiovascular Alterations in Normal and Preeclamptic Pregnancy
Editors' comment: We welcome the addition of a new coauthor to this chapter, Alisse Hauspurg MD, who brings expertise in Maternal Fetal Medicine with a focus on hypertensive disorders of pregnancy. The chapter has been revised and updated to include the new literature that emerged on the topic since the previous version in the fourth edition.
Introduction
There are striking physiologic cardiovascular changes during pregnancy that ensure adequate uterine blood flow, as well as appropriate oxygenation and nutrient delivery to the fetus. These changes are both anticipatory and compensatory, and they allow the mother to function normally during this altered physiologic state. Both knowledge of and understanding the roles of these changes are particularly critical if strategies are to be developed to manage pregnant women with chronic or new-onset hypertension and especially preeclampsia. Thus, how the preeclampsia syndrome impacts the cardiovascular system may be integral to appropriate therapy, but, as we shall see, studies designed to document effects of preeclampsia on the cardiovascular system have not always produced the same results. This chapter commences with a review of normal cardiac and hemodynamic function during pregnancy followed by a survey of knowledge regarding cardiac performance and vascular changes in preeclampsia, focusing on recent progress, much made possible by advances in noninvasive technology. Finally, we discuss the potential of using pregnancy-associated aberrant responses to predict maternal cardiovascular disease risk later in life.
Hemodynamics and Cardiac Function in Normal Pregnancy
More than 100 years ago, Lindhard, reporting on normal cardiovascular adaptations in pregnancy, described a 50% increase in cardiac output as measured by a dye-dilution technique. Since then, multiple methodologies have been employed to assess cardiovascular function in pregnancy and have resulted in a myriad of findings. The “gold standard” for such evaluation remains flow-directed pulmonary artery catheters using thermodilution methodology. Given the invasive nature of these techniques, only cross-sectional investigations are feasible. Fortunately, noninvasive M-mode echocardiography and continuous and pulsed-wave Doppler techniques, validated against an invasive technique, permit serial determinations throughout both normal and abnormal pregnancy.
One must be cautious in regard to several methodological issues that impact cardiovascular parameters in pregnancy. These include maternal posture during data collection, whether or not she received fluids or vasoactive medications prior to data acquisition, and whether there is active labor. In addition, maternal body habitus can also affect cardiac measurements. Some, but not all, investigations have controlled for these potential confounding issues.
Systemic Arterial Hemodynamics in Normal Pregnancy
There are significant decreases in both systolic and diastolic blood pressure, noted as early as 5 weeks' gestation ( Fig. 11.1 ). Interestingly, Chapman et al. noted a significant decrease in blood pressure during the luteal compared with the follicular phase of the menstrual cycle—data suggesting that a hormonal signal of maternal origin underlies the fall in blood pressure. This fall in pressure persists and may decline even further after conception. The decrease in blood pressure during pregnancy is characterized as follows: Decrements in diastolic levels exceed those in systolic levels, the former averaging 10 mm Hg below baseline value. Mean blood pressure reaches a nadir at 16–20 weeks, these changes persisting to the third trimester , ( Figs. 11.1 and 11.2 ). In the mid-third trimester, blood pressure rises gradually, often approaching prepregnancy values. There are diurnal fluctuations in normal pregnancy, similar to patterns in the nonpregnant state, the nadir occurring at night. Finally, all these observations have also been verified using 24-h ambulatory blood pressure monitoring protocols ( Fig. 11.3A and B ).
Cardiac output increases 35%–50% during gestation, as much as one-half of this increase being established by the eighth gestational week. The earliest evidence of this change—in parallel with decreases in mean arterial pressure—can be detected in the luteal phase of the menstrual cycle. If conception does not occur, then there is a significant reversal of all these changes, detectable in the next follicular phase. These data implicate the corpus luteum in the observed changes and attest to a hormonal role of maternal origin in the early cardiovascular changes of pregnancy.
The significant increase in cardiac output is well established by gestational week 5, rising further to 50% above prepregnancy values by gestational weeks 16–20, then increasing slowly or plateauing until term , , , , , , ( Fig. 11.4 ). Several investigators have noted different patterns, including a decrease in cardiac output from the peak pregnancy value when term approaches , , , ; some of these discrepancies might relate to failing to control posture or to inappropriate correction for body surface area. ,
Stroke volume and heart rate, the two determinants of cardiac output, appear to rise in parallel, with the increases apparent by 5–8 weeks' gestation. , , Stroke volume continues to increase until gestational week 16, plateauing thereafter, while heart rate continues to increase slowly into the third trimester , , ( Fig. 11.4 ).
Capeless and Clapp noted that 50% of the increase in cardiac output had occurred by gestational week 8, this early change primarily due to increased stroke volume (not to heart rate changes), perhaps, a consequence of the fact that the study subjects were healthy and fit young women. These investigators also noted that multiparas had a greater rise and rate of change in stroke volume compared with nulliparas, as well as a greater drop in systemic vascular resistance, but there was no differential effect on heart rate.
Postural changes can impact heart rate, blood pressure, and cardiac output. Both heart rate and blood pressure are significantly lower in lateral recumbency, while cardiac output is increased in this position. There is a reduction in cardiac output upon standing, noted in the first trimester, which becomes significantly attenuated in the second trimester and absent by the mid-third trimester. Intravascular volume progressively increases up to 40% above prepregnant levels, perhaps contributing to the amelioration of postural changes with advancing gestation (see Chapter 15 ).
To summarize, most evidence supports the following scenario of physiologic cardiovascular changes during pregnancy: there is an early decrease in systolic, diastolic, and mean blood pressures (the diastolic decrement exceeding the systolic decrement), an early increase in cardiac output that continues to rise or plateau into the third trimester, with increases in both stroke volume and heart rate contributing to this increase in cardiac output. The increase in stroke volume is primarily driven by the fall in systemic vascular resistance (vide infra).
Venous System in Normal Pregnancy
Mean Circulatory Filling Pressure
Venous return to the right heart maintains filling pressure, permitting adaptation to changing cardiac output requirements. A prerequisite for such regulation is that the vascular bed with appropriate tone should be adequately filled with blood. The mean circulatory filling pressure (MCFP) characterizes this steady-state venocardiac filling. The MCFP is the pressure recorded in the vascular tree at equilibrium and in the absence of any blood flow, which is the pressure in the circulation after the heart has been arrested and the system has come into equilibrium. The MCFP thus provides an indication of the relationship between changes in blood volume compared with the size of the circulatory compartment and, as such, indicates to what extent the vascular compartment accommodates the large gestational increases in total blood volume. Venous smooth muscle activation/relaxation and changes in blood volume are mechanisms for changing the MCFP.
Because measurement of MCFP requires stopping the heart, it follows that results must be derived from animal studies. Thus, one must be circumspect about their relevance to human pregnancy, as not only may we be dealing with species differences, but also all of these experiments concerning MCFP were conducted in anesthetized animals.
The MCFP is slightly, but significantly, elevated in pregnant dogs, rabbits, sheep, and guinea pigs, , though one guinea pig study found no differences compared with the nonpregnant state. Furthermore, pregnant dogs respond to epinephrine infusions with a rise in MCFP in a manner similar to nonpregnant controls, suggesting that they are able to increase their vascular tone normally. Also, the slope relating MCFP to changes in blood volume in most studies appears not to be altered by gestation, , , , rather the blood volume (BV)-MCFP relationship is merely shifted to the right, that is, there is increased unstressed volume. One group, however, did suggest a decrease in the slope of the BV-MCFP relationship, interpreted as increased compliance. Both increased venous unstressed volume and compliance permit the large increases in intravascular volume, characteristic of gestation, to occur with very little rise in MCFP. As a whole, the increased MCFP with the aforementioned changes in venous unstressed volume and compliance can be interpreted as showing that the “stressed”—i.e., distending—component of the intravascular volume is elevated in pregnancy.
The higher MCFP has led some to suggest that the increased cardiac output may be secondary to relative overfilling of the circulatory system during pregnancy , This is discussed in detail in Chapter 15 with considerations given to whether the gestational increase in blood volume should be considered “underfill,” “overfill,” or “normal fill.” Because the BVMCFP relationship represents a measure of total circulatory compliance, and for practical purposes total body venous compliance, such data would suggest that venous tone was unaltered in pregnancy, a finding that supports those who see pregnancy as vascular overfill. Concerning the meaning of MCFP in these discussions, one must recall the circumstances of how this index is measured and the many interpretative problems with these anesthetized animal preparations.
In terms of cardiovascular homeostasis, the “active” regulation of capacitance remains a key question during pregnancy as this is one of the important mechanisms that influence venous return of blood to the heart, the systemic reflex capacitance in humans estimated at ∼5 mL/kg. The densely innervated mesenteric venous microcirculation appears to have a key function in controlling changes in vascular capacity. For example, most of the BV shift in the intestinal vascular bed during activation of the baroreceptor reflex occurs in the intestinal venules.
Venous Tone Regulation
The venous system in pregnancy appears to be a neglected area of research. Hohmann et al. studied adrenergic regulation of venous capacitance in pregnant and pseudopregnant rats, noting a progressive decline in the sensitivity to adrenergic nerve stimulation from cycling to late gestation. The reduced sympathetic nerve response was associated with marked increases in sensitivity to exogenously applied epinephrine during pregnancy, suggesting denervation supersensitivity .
It should be noted that venous pressure–volume or wall stress–strain relationships cannot accurately be characterized, either in vivo or in vitro, without defining the contractile state of the vascular smooth muscle. Also, measurements made in vivo cannot distinguish between wall structural changes and those caused by differences in venous tone. In one study, where vascular smooth muscle was inactivated prior to assessing stress–strain relationships in pregnant rodents, the compliance of the mesenteric capacitance veins decreased by 40%. The unstressed volume, however, doubled in comparison to the nonpregnant females.
In human studies, noninvasive measures suggest that venous distensibility increases with pregnancy in some investigations, but not in others. We could locate no longitudinal measures of human venous distensibility that included preconception values. It is interesting to note that left ventricular filling is not compromised despite increased venous distensibility; left ventricular end-diastolic volume is either increased or unchanged (vide infra). This increased or preserved left ventricular filling may be a result of a significant increase of cardiovascular volume and a reduction in resistance to venous return in normal pregnancy.
In summary, despite the importance of venous function to cardiovascular volume homeostasis, knowledge of either the normal or pathophysiologic status of this system is quite limited. It appears that venous distensibility (compliance) increases during gestation. Animal data, obtained under less-than-ideal experimental conditions, suggest that the increased vascular capacitance does not quite accommodate the increase in blood volume (“overfill”). Whether MCFP changes in human gestation is unknown. Information on sympathetic regulation of venous function in terms of regulating both venous return and fluid exchange at the capillary bed would be of interest, but again information is spotty.
Systemic Arterial Properties in Normal Pregnancy
The gestational increase in cardiac output and decrement in blood pressure have traditionally been ascribed to the marked decrease in total systemic vascular resistance that is apparent early in gestation. , , , It should be recognized, however, that other changes may be involved. For example, both left ventricular and systemic arterial mechanical properties —ventricular afterload—have a potential to alter systemic hemodynamics. Afterload, or the arterial system load the heart experiences, is the mechanical opposition experienced by the blood ejected from the left ventricle. This opposition can be considered to have two components—one steady, the other pulsatile. The steady component, quantified in terms of total systemic vascular resistance, is determined by the properties of the small-caliber resistance vessels, for example, effective cross-sectional area, and blood rheological properties, for example, viscosity.
Due to the pulsatile nature of cardiac ejection, oscillations in pressure and flow exist throughout the arterial tree and thus the pulsatile component of the arterial load needs to be considered. Physically, the pulsatile arterial load is determined by the (visco)elastic properties of the arterial vessel wall, architectural features of the arterial circulation, that is, the network of branching tubes, and blood rheological properties. Quantitative indices of pulsatile load include the global arterial compliance, aortic characteristic impedance, and measures of wave propagation and reflection. Global arterial compliance is a measure of the reservoir properties of both the conduit and peripheral arterial tree. In contrast to global arterial compliance, which is a property belonging to the entire circulation, characteristic impedance quantifies a local property pertaining to the site of pressure/flow measurement, being determined by local vascular wall stiffness and geometric properties. Pulse wave velocity and global reflection coefficient are indices often used to describe wave propagation and reflection within the arterial tree. Understanding the interplay of both steady and pulsatile components should lead to a better grasp of cardiovascular performance in pregnancy with its marked changes in both components.
To this end, Poppas et al. serially studied 14 healthy, normotensive women throughout pregnancy and 8 weeks postpartum using noninvasive measures of instantaneous aortic pressure and flow velocities to assess both conduit and peripheral vessels. These investigators verified that systemic vascular resistance, the steady component of the arterial load, decreases very early in pregnancy and continues to decrease significantly through the remainder of pregnancy, though less so in the latter weeks of gestation ( Fig. 11.5 ). Global arterial compliance increased by 30% during the first trimester and was maintained thereafter throughout pregnancy, temporally relating to the decreased systemic vascular resistance. By 8 weeks' postpartum, global compliance returned to normal levels ( Fig. 11.5 ). There was a tendency for aortic characteristic impedance to fall, and the magnitude of arterial wave reflections was reduced during late pregnancy, along with a delay in the timing of reflected waves. Similar results documenting increased compliance have been noted in pregnant animal models , , and in other studies of pregnant humans, , as well as nonpregnant humans subjected to high-dose estrogen adminstration. Mone et al. also noted decreased characteristic impedance in a cohort of 33 normal pregnant women.
It is thus clear that both steady and pulsatile arterial load decrease during normal pregnancy, indicating a state of peripheral vasodilatation and generalized vasorelaxation that involves both the peripheral (resistance) vessels and conduit vessels. The magnitudes of the fall in systemic vascular resistance and the rise in cardiac output seem to be equivalent, resulting in a very small change (fall) in mean arterial pressure. The decrement in pulsatile arterial load—that is, increased global compliance, decreased characteristic impedance, and decreased reflection coefficient—appears to be primarily due to a generalized increase in vascular distensibility, which, in turn, may be related to reduced smooth muscle tone and vascular remodeling.
Left Ventricular Properties in Normal Pregnancy
Structural Properties
Left ventricular mass increases in normal pregnancy. The increase has been described by some , , , , as modest, averaging 10%–20%, while others , , have reported increments as great as 40%. An increase in ventricular mass should contribute to an increase in power as described below. Of note, in most studies the increase in mass does not meet criteria for ventricular hypertrophy—defined as >2 SD above the mean for normal population—as might occur, for example, in patients with chronic hypertension. Also, ventricular mass reverts to nonpregnant values postpartum. There is an increase in left ventricular end-diastolic chamber diameter or volume noted by many, , , but not all , , , , investigators.
Normal pregnancy is associated with an increase in the cross-sectional area of the left ventricular outflow tract, measured at the aortic annulus. , , , , , , , Thus, it is important to assess aortic diameter at the time of echocardiography in longitudinal studies. These findings further highlight the risks the normal changes in pregnancy create for women with diseases known to be associated with a compromised aortic root, namely Marfan or Turner syndromes. In these women, pregnancy may precipitate aortic rupture or dissection. ,
Systolic Properties
Evaluation of left ventricular systolic properties in pregnancy (myocardial contractility in particular) has produced conflicting results. Use of traditional ejection-phase indices of left ventricular performance is problematic as these indices are unable to distinguish alterations in contractility from changes in ventricular load. , , Thus, some of the variability in the results related to the assessment of left ventricular myocardial contractility may be attributable to the use of load-dependent indices.
Lang et al. studied 10 normally pregnant women in early labor and again at 1 day and 4 weeks postpartum. These investigators quantified left ventricular myocardial contractility using the measurements of end-systolic wall stress (σ) and rate-corrected velocity of fiber shortening (Vcf) ( Fig. 11.6 ). Note, the σ–Vcf relationship yields a preload-independent and afterload-adjusted characterization of left ventricular myocardial contractility. The σ and Vcf data from individual subjects were compared to a nomogram, i.e., a σ–Vcf relationship constructed by studying a large group of normal, nonpregnant individuals, both in their basal state and after pharmacologic manipulation of afterload and preload. The σ–Vcf data points for the normal pregnant women were shifted rightward and downward, remaining superimposed on the nomogram, indicating a decrease in afterload without any changes in left ventricular contractility ( Fig. 11.6 ). These observations were verified by Poppas et al., who reported an invariant left ventricular myocardial contractility throughout pregnancy in a cohort of normal pregnant women. Finally, Simmons et al. similarly demonstrated unchanged contractility in 44 pregnant women.
Some studies have claimed that left ventricular myocardial contractility changes during normal pregnancy. For example, Mone et al. have reported a reversible fall in left ventricular myocardial contractility. This conclusion was based on the observation that Vcf progressively diminished during gestation—by 7% at term—even though σ was declining over the same time period—by 15% at term. However, a comparison with the nomogram indicated that the group-averaged values of σ–Vcf points during pregnancy were above the normal contractility line and were within the statistical bounds of the normal (nonpregnant) population. Similarly, Gilson et al. have reported an enhanced left ventricular myocardial contractility. While there were no significant changes in Vcf, σ decreased by 12% over the observation period from early to late gestation. This observation, if anything, would imply decreased myocardial contractility. Their conclusion of enhanced contractility was based upon the observed decrease in σ/Vcf ratio, which they claim to be a load-independent index of myocardial contractility as proposed by Colan et al. Interestingly, Colan et al. never proposed the σ/Vcf ratio as an index of myocardial contractility; instead, they used the position of the σ–Vcf point relative to the normal contractility line to quantify contractility in an individual subject. Furthermore, the σ/Vcf ratio is highly load-sensitive; it will change significantly as one moves along a given σ–Vcf relationship, that is, by definition, fixed myocardial contractility. Thus, the conclusion of enhanced myocardial contractility by Gilson et al. appears to be erroneous.
To summarize, most of the evidence supports a conclusion that left ventricular myocardial contractility, as assessed by load-independent indices, is essentially unchanged in normal gestation. The data would be more secure, however, if the contractility nomogram used in future studies was derived exclusively from a female population of reproductive age.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here