Keywordspreeclampsia, cardiovascular system, systemic arterial circulation, hemodynamics, left ventricular mechanics, pregnancy response and later-life cardiovascular disease risk
Editors’ comment: The heart was a brief bystander in Chesley’s original text. Evolving research on dissecting changes in cardiac function during gestation as well as a new school that claimed that exaggeration of the normal increase in cardiac output was a factor that led to preeclampsia emerged as the second edition went to press. These were refined and discussed further in the third edition, reflecting the fact that the technology by which we gauge the cardiac system had been markedly improved during the early years of this millennium. Progress has continued and the fourth edition contains interesting and exciting new material, some representing the research productivity of Drs. Hibbard and Shroff.
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 compensatory mechanisms 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 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 cardiovascular disease risk later in life.
Hemodynamics and Cardiac Function in Normal Pregnancy
Nearly 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. 14.1 ). 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 a hormonal origin of the fall in blood pressure that persists and increases 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 nadirs at 16–20 weeks, these changes persisting to the third trimester ( Figs. 14.1 and 14.2 ). 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-hour ambulatory blood pressure monitoring protocols ( Fig. 14.3A, B ).
Cardiac output increases 35–50% during gestation, half or more 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 (see Fig. 15.1 ). These data implicate the corpus luteum in the observed changes, and attest to a hormonal role 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. 14.4 ). 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 correct for body surface area.
Stroke volume and heart rate, the two determinants of cardiac output, appear to rise sequentially, 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. 14.4 ).
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). 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 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 is progressively amplified up to 40%, perhaps contributing to the aforementioned changes (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, and increases in both stroke volume and heart rate contributing to this increase in cardiac output.
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 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 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 blood volume–MCFP relationships represent a measure of total circulatory compliance, and for practical purposes total body venous compliance, such data would suggest 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 blood volume 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.
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. Thus, influences on the venous system by pregnancy are limited, and they are even more limited regarding changes in preeclampsia.
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 arterial compliance, which is a global property (belonging to the entire circulation), characteristic impedance quantifies a local property (belonging 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 normal, 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. 14.5 ). 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. 14.5 ). 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. Mone et al. also noted decreased characteristic impedance in a cohort of 33 normally 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
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 a mild increase in left ventricular end-diastolic chamber diameter 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, viz., Marfan or Turner syndromes. In these women, pregnancy may precipitate aortic rupture or dissection .
Evaluation of left ventricular myocardial contractility in pregnancy 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. 14.6 ). 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. 14.6 ). 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, the latter investigators 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.
In contrast to systolic function, left ventricular diastolic function has infrequently been the primary focus of studies in normal pregnancy, although this aspect is also important in evaluating cardiac function. Most common evaluation of left ventricular diastolic function is based on the measurement of transmitral inflow velocity by Doppler echocardiography. These transmitral inflow velocity-based indices, however, are load and heart rate dependent. Diastolic function of the left ventricle was assessed by Fok et al. in a prospective longitudinal investigation of 29 pregnant women using tissue Doppler imaging (TDI). TDI-based indices are better suited for the evaluation of myocardial relaxation and are relatively independent of preload, although one pitfall of this technique is that it is angle dependent and may have high interobserver variability. Data obtained in each trimester and postpartum demonstrated that left ventricular diastolic function was preserved, with augmented late diastolic function accommodating the increased preload of normal gestation. Similar findings were noted in cross-sectional trials using the same methodology, but carried out to answer different questions, in normal pregnant control women.
Coupling between Left Ventricle and Systemic Arterial Circulation in Normal Pregnancy
From the mean pressure-flow perspective, the coupled left ventricle–arterial circulation system produces significantly higher cardiac output during normal pregnancy, with little change in mean blood pressure, although a slight decrease is typically observed. This coupled equilibrium of mean pressure and flow is achieved by a significant peripheral vasodilatation (reduced systemic vascular resistance) and increases in heart rate, left ventricular preload (end-diastolic volume), and muscle mass, without any significant changes in left ventricular myocardial contractility.
From the perspective of pulsatile hemodynamics, mathematical simulation-based analysis indicates that if the fall in the steady arterial load – the decrease in systemic vascular resistance – was not accompanied by that in pulsatile arterial load, for example, increase in global compliance, then arterial pulse pressure would have increased significantly, with the decrement in diastolic pressure being significantly greater than that in systolic pressure. Thus, the increase in global arterial compliance that accompanies the profound peripheral vasodilatation prevents the undesirable increase in pulse pressure and diastolic hypotension that can compromise myocardial perfusion.
Left ventricular hydraulic power, another functional index of the coupled left ventricle–arterial circulation system, has been evaluated during normal pregnancy. Two components constitute total power – steady and oscillatory power. The oscillatory component is considered to be wasted power as it does not result in net forward flow of the blood. Thus, the ratio of the oscillatory to total power is often used as an index of inefficiency of the coupled left ventricle–arterial circulation system. Although both total and oscillatory power increased significantly throughout pregnancy, peaking in the third trimester ( Fig. 14.7 ), the ratio of the oscillatory to total power did not change significantly throughout gestation. The aforementioned mathematical simulation-based analysis predicted that this ratio would have doubled, i.e., efficiency decreased by a factor of two, had the increase in global arterial compliance not accompanied the fall in systemic vascular resistance.
In summary, the various systemic arterial and left ventricular mechanical properties undergo coordinated changes in normal pregnancy that result in significantly increased cardiac output with little change in mean and pulse pressures and ventriculo-arterial coupling efficiency. The fall in the pulsatile arterial load (the increase in global arterial compliance) that accompanies the decrease in the steady load (systemic vascular resistance) in normal pregnancy is considered to be an adaptive response. There are at least three reasons for this: (1) markedly increased intravascular volume can be accommodated without a concomitant increase in mean arterial pressure, (2) increase in pulse pressure and diastolic hypotension are prevented, and (3) the efficiency of the mechanical energy transfer from the left ventricle to the arterial circulation is maintained.
Hemodynamics and Cardiac Function in Preeclampsia
As summarized above, assessment of the cardiovascular system in normal pregnancy is fraught with methodological and design pitfalls. Here we note emphatically that such problems and challenges are even greater when studying women with preeclampsia. For example, as discussed in Chapter 1 , the true diagnosis of preeclampsia is never certain by clinical criteria alone. There may be other concomitant pathology simultaneously influencing the cardiovascular system such as renal disease or diabetes. Finally, no matter how well the experiments are designed, certain confounders may be difficult to eliminate or circumvent, as for example treatment with magnesium sulfate or other antiseizure agents, antihypertensive medications, or parenteral fluid administration, as well as whether or not the preeclamptic woman is in active labor.
Systemic Arterial Hemodynamics in Preeclampsia
While preeclampsia is characterized by the development of hypertension, typically late in gestation, many, but not all, women destined to develop preeclampsia have been documented to have an elevated mean blood pressure when compared with normotensive women – an observation present as early as the ninth gestational week ( Fig. 14.2 ). These differences have also been shown using ambulatory blood pressure technology ( Fig. 14.3 ). Clearly, elevated blood pressure in early pregnancy is a risk marker for developing preeclampsia later; however, blood pressure values alone are a poor predictor for actually determining who will develop preeclampsia.
A change in the normal diurnal pattern of blood pressure in women destined to develop preeclampsia has been noted, with either obliteration of the decrease in nocturnal pressure or a shift in the timing of the blood pressure nadir. Recently alterations in cardiovascular regulatory behavior have been suggested to predict preeclampsia by assessing systolic as well as diastolic beat-to-beat pressures and heart rate by variability and coupling analysis. Discriminant function analysis of the parameters predicted preeclampsia with an 88% sensitivity and specificity, and if assessment of uterine artery resistance was added, a 70% positive-predictive value at 18–26 weeks gestation was realized.
As discussed above, normal pregnancy is accompanied by increased intravascular volume, high cardiac output, and vasodilatation – a low-resistance systemic circulation. With the onset of overt preeclampsia there is a shift to a low-output, high-resistance state, and intravascular volume is significantly lower than in the normal pregnant state ( Chapter 15 ). This traditional characterization of preeclampsia as a state of decreased intravascular volume, lower cardiac output, and vasoconstriction is not observed by all investigators. A myriad of problems may contribute to the variable observations, including manipulation of volume status prior to evaluation, that can alter the pathophysiological picture present before the treatment.
The dilemma alluded to above, for example, can be appreciated by a review of studies during the 1980s performed using “gold standard” invasive monitoring with Swan–Ganz pulmonary artery catheters that produced markedly contrasting results. Some investigators noted decreased cardiac output, others increased or unchanged, and there was wide variation in the measured peripheral vascular resistance. That said, a landmark investigation by Visser and Wallenburg appears to have pinpointed the reasons for these diverse findings. Two unique features distinguish this work. First, they compared a group of untreated or “virgin” preeclamptic women to a cohort of treated preeclamptics, and second, the number of subjects included – 87 untreated and 47 treated – appears to be the largest investigation using invasive technology and reported by 2014. It is also unlikely that this investigation will ever be repeated because pulmonary artery catheter monitoring is rarely used today. Instead, the wide availability of noninvasive techniques for assessment has replaced the invasive ones.
Visser and Wallenburg carefully chose their subjects, using strict criteria and only selecting women with diastolic pressure of 100 mm Hg measured twice four hours apart, proteinuria≥0.5 g/L, onset≥20 weeks gestation, and complete recovery postpartum. Patients with medical disorders such as chronic hypertension, cardiac or renal disease were excluded. Patients receiving intravenous fluids, antihypertensive medication, antiseizure therapy or any other type of medication were considered “treated,” while those women who had not yet received any of the aforementioned therapies were the “pure (or virgin) preeclamptic” group. These women were not randomized to treatment groups. Finally, a group of normotensive women studied in another protocol were used for further comparison. (Of note, studying consenting normal pregnant volunteers with central monitoring was defended in the 1980s, the risk believed low, and the need to obtain normative data to improve intensive care monitoring and treatment of pregnant women was believed to be consistent with equipoise considerations. The status of noninvasive technology, we believe, would currently preclude such studies today.)
Table 14.1 summarizes the hemodynamic measurements of Visser and Wallenburg. As expected, mean arterial pressure was highest in the untreated preeclamptic group – 125 mm Hg – underscoring disease severity in relation to treated preeclamptics and normotensive pregnancies. Note the remarkably consistent hemodynamic parameters in the “virgin” preeclamptics, that is: a significantly decreased cardiac index, as well as the marked and significantly increased systemic vascular resistance. This contrasts with the results from treated preeclamptics. Note further that capillary wedge pressure remained normal. These findings strongly support the concept of preeclampsia being predominantly associated with low cardiac output, markedly increased systemic resistance, and an increased afterload, and suggest explanations for the variable findings of others. This signal work confirms the same group’s preliminary findings in a smaller group studied previously.
|Preeclamptics, Untreated ( n =87)||p a||Normotensive Controls ( n =10)||p b||Preeclamptics, Treated ( n =47)|
|Mean intra-arterial pressure (mm Hg)||125 (92–156)||<0.001||83 (81–89)||<0.001||120 (80–154) c|
|Cardiac index (L min −1 m −2 )||3.3 (2.0–5.3)||<0.001||4.2 (3.5–4.6)||NS||4.3 (2.4–7.6) c|
|Systemic vascular resistance index (dyne s cm −5 m 2 )||3003 (1771–5225)||<0.001||1560 (1430–2019)||<0.005||2212 (1057–3688) c|
|Pulmonary capillary wedge pressure (mm Hg)||7 (1–20)||NS||5 (1–8)||<0.05||7 (0–25)|
Lang et al., using noninvasive techniques to compare 10 severe preeclamptics with 10 normotensive pregnant women, each evaluated in labor, and again 1 day and 4 weeks postpartum, obtained similar results. They reported significantly decreased cardiac output and increased systemic vascular resistance during preeclampsia, and both groups had similar hemodynamic profiles at postpartum follow-up.
While the cardiovascular changes during overt preeclampsia seem clear, there are differences of opinions regarding the changes that precede clinical presentation of the disease. The general impression is that there is evidence of a vasoconstrictor state well before overt disease manifests. For instance increased sensitivity to pressor substances, increments in circulating antiangiogenic factors that affect the vasculature in a manner that opposes vasodilatation, and lower intravascular volume, precede the disease by many weeks. These issues are explored further elsewhere in the text in Chapter 6 , Chapter 15 .
Although this “vasoconstricted” state with preeclampsia is more widely accepted, there is an alternate view that women destined to develop preeclampsia have an exaggeration of the normal increase in cardiac output in early pregnancy. In this scenario, championed by Easterling and Bosio and their colleagues, preeclampsia is the end result of a pregnancy originally marked by an excessive increase in cardiac output with an exaggerated compensatory decrease in systemic peripheral resistance. In this regard, they liken the preclinical phase of preeclampsia to that preceding overt essential hypertension. In the latter, Messerli et al. described this prehypertensive phase as one of increased cardiac output accompanied by a reflex decrease in systemic resistance, a protective mechanism against the appearance of elevated blood pressure. Eventually this autoregulation mechanism fails, afterload increases, cardiac output decreases, and hypertension becomes manifest. Thus in the combined views of Easterling and Bosio and their coworkers, preeclampsia would occur in pregnant women with exaggerated increases in cardiac output, and normal or slightly increased gestational falls in peripheral vascular resistance, but at the time the disease becomes overt there is a “crossover” to a high-resistance low-output state. If this theory were to prove correct, it would be logical to try to identify women with exaggerated increases in cardiac output early in pregnancy and treat them with drugs that lower output such as beta-blockers, and indeed such a study has been done.
There are, however, a number of problems with the theories of Easterling and Bosio. First, Easterling et al. studied nulliparous women serially using noninvasive techniques to measure mean arterial pressure and cardiac output. Of 179 women, 89 had normal pregnancies, 9 developed preeclampsia, and 81 had gestational hypertension. Before disease manifestations, the women destined to develop preeclampsia had higher mean arterial pressures and cardiac output, with lower systemic resistance, albeit the latter was not significant. In this study there were no significant changes detected in either the high cardiac output state or in the reduced systemic resistance when overt signs and symptoms of preeclampsia occurred. The higher initial blood pressure in the eventual preeclamptics is consistent with findings of other investigators, but the early elevated cardiac output with normal or reduced vascular resistance had not been described previously. Of concern, there was a high drop-out rate, and only nine women developed preeclampsia, mainly mild disease – they were delivered at a mean of 39.4 weeks. Also, neonatal birth weight was similar to the controls. Other concerns were the use of a 1+qualitative determination to define proteinuria.
Second, Easterling et al. used a continuous-wave Doppler ultrasound system with no range-gating or imaging capabilities, and measurements of the aortic annulus were obtained by A-mode ultrasound, measurements that are more prone to angulation errors. The preeclamptic women had a much higher body mass than the control population, and there was no correction for this factor in calculating cardiac output. Specifically, the preeclamptics were on average 12 kg heavier than the nonpreeclamptic women – BMI 29.8 kg/m 2 vs. 24.9 kg/m 2 calculated from the data provided – and thus obesity, a factor known to increase cardiac output, could explain the increments recorded. Finally, the authors did not provide results for the 89 women who developed gestational hypertension, a complication of pregnancy in many women who eventually manifest essential hypertension. Given this remarkably high incidence of women with gestational hypertension in the study, viz., nearly half, comparisons of cardiac output and vascular resistance between the two hypertensive groups would have been instructive.
There are similar problems with the study by Bosio et al. It was much larger with 400 subjects, and it was a longitudinal survey that utilized similar noninvasive techniques. They too describe a high cardiac output state prior to evidence of clinical disease in the 20 women who developed preeclampsia, but here systemic vascular resistance in the latent phase was definitely normal. After the “cross-over,” however, and similar to Visser and Wallenberg and Lang et al., but unlike Easterling et al., they noted markedly decreased cardiac output and increased systemic vascular resistance. Bosio et al. did not correct cardiac output for maternal weight, but stated that even after adjusting for BMI statistical significance was maintained; however, these data are not presented. The group of 24 women who developed gestational hypertension remained with high cardiac output after disease manifestation ( Fig. 14.8 ). These investigators have suggested that the hemodynamic changes promote endothelial injury and trigger the low-output vasoconstricted state of clinical disease.
More recently, Dennis et al. studied 40 “untreated” preeclamptic women and also reported increased cardiac output and increased cardiac contractility defined by fractional shortening, as well as reduced diastolic function. But the preeclamptic women had significantly greater BMIs. In addition, information regarding administration of intravenous fluids or magnesium sulfate was not given, and they did not correct for loading conditions in assessing contractility.
Because of this “minority” theory, some have postulated that treatment with beta-receptor blocking drugs for women with exaggerated cardiac output in early pregnancy might prevent preeclampsia. It appears that this suggestion might be premature. Carr et al. reported that women at risk of preeclampsia with high cardiac output treated with atenolol have a blunted rise in sFlt levels compared with those at low risk. It is problematic, however, that this was a nonrandomized, secondary analysis that included a small number of women. More importantly, these investigators did not demonstrate prevention of preeclampsia. Thus, a prospective randomized trial is needed to further study this theorem. In addition, it is necessary to explain how this theory is compatible with overwhelming evidence that the preclinical state of preeclampsia is one marked by increased pressor responses, lower intravascular volume, and increased levels of circulating antiangiogenic proteins that impair vasodilatation.
Systemic Arterial Properties in Preeclampsia
The earlier studies of the effects of preeclampsia on systemic arterial load have been described mostly in terms of the steady component: peripheral vasoconstriction as indicated by an increase in systemic vascular resistance. In the previous edition, we introduced more recent approaches that included assessment of the pulsatile component of arterial load and the complex interactions of the components of the cardiovascular system in the face of a low-output, high-afterload disease state. Hibbard and colleagues performed a cross-sectional study comparing preeclamptics, chronic hypertensives with superimposed preeclampsia, and normotensive women admitted in preterm labor. Because all women were given magnesium sulfate for either seizure prophylaxis or tocolysis, two additional control groups were included to eliminate confounding factors. One was that of normal laboring women with epidural analgesia and the second group included normotensive laboring women who were given neither epidural analgesia nor magnesium sulfate. This study confirmed that total vascular resistance, the steady component of the arterial load, was significantly elevated in both hypertensive groups, but more so in the chronic hypertensives with superimposed preeclampsia. Global arterial compliance was significantly lower in the pure preeclamptic group and with an even greater decrement in chronic hypertensive women with superimposed preeclampsia ( Fig. 14.9 ). The authors further showed that a substantial component of the decreased global compliance was not completely attributable to the rise in blood pressure, but independently related to preeclampsia per se ( Fig. 14.10 ). These findings indicated the overall reservoir properties of the systemic arterial circulation to be compromised. Lower compliance (or higher stiffness) was observed for large conduit arteries as well. For example, the magnitude of the first harmonic of aortic input impedance ( Z ) was significantly elevated in both hypertensive groups ( Fig. 14.11 ) and aortic characteristic impedance tended to be greater in both hypertensive groups, though not significantly so. Reflection index (RI), a measure of wave reflections within the arterial system, was increased in the preeclamptics and more so in those with chronic hypertension with superimposed preeclampsia. Thus, during the late stages of preeclampsia, both steady and pulsatile components of arterial load are elevated as compared to the normal pregnancy.