Changes in hemodynamics, ventricular remodeling, and ventricular contractility during normal pregnancy: A longitudinal study

Changes in Hemodynamics, Ventricular Remodeling, and Ventricular Contractility During Noimal Pregnancy: A Longitudinal Study GEORGE 1. GILSON, MD, SARAH SAMAAN, CLIFFORD

Franz the Division of Matmal Fetal Medicine, Depautment of Obstetrics and Gynecology, Division qf Cardiology, Department of Medicine, and the Department ofMathematics and Statistics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. Supported in part by the Dedicated Healtk Research Funds of the University of Nezu Mexico School of Medicine, the Department cf Obstetrics and Gynecology of the University of New Mexico Health Sciences Center, and by NCRR-GCRC Grant MO1 RR00997.

NO.

H. CRAWFORD,

MD,

R. QUALLS, PhD, AND LUlS B. CURET, MD

Objective: To investigate the hemodynamic changes occurring in normal pregnancy and to see if these changes were associated with an increase in myocardial contractility. Methods: In a longitudinal study, primigravidas were studied with echocardiography in early (15 + 1.8 weeks), mid (26 rt 1.2 weeks), and late (36 f 1.0 weeks) gestation, as well as at 6 weeks postpartum. Cardiac dimensions were measured with two-dimensional and M-mode echocardiography and hemodynamic indices were calculated. All measurements were made with subjects in the left lateral decubitus position. Statistical analysis was performed with repeated measures analysis of variance. Results: Seventy-six women with normal pregnancy outcomes completed all four studies. From the baseline study to late gestation, an increase in cardiac output of 27% (from [mean f standard error] 4.2 f 0.1 to 5.8 f 0.2 L/min, P = .OOl), and a decrease in total peripheral resistance of 33% (from 1356 -C 69 to 941 f 37 dynes/second cmm5, P = .OOl) occurred. Over this same time period, left ventricular function, while demonstrating a small and non-significant increase in velocity of circumferential fiber shortening (from 1.25 f 0.02 to 1.27 -C 0.02 cm/second), revealed a 12% decrease in wall stress (from 36.3 + 1.0 to 31.9 + 1.0 g/cm’, P = .OOl) and a 13% decrease in the load-independent wall stress to velocity of circumferential fiber shortening ratio (from 30.0 f 1.2 to 26.1 f 1.0, P = .Ol), implying enhanced intrinsic myocardial contractility. Conclusion: Normal pregnancy is characterized by enhanced myocardial performance. (Obstet Gynecol 1997;89:

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957-62. 0 1997 by The American and Gynecologists.)

College

of Obstetricians

Remarkable changes in cardiovascular function are known to occur during the course of normal pregnanCY.l-3 Conflicting conclusions exist regarding the time course and the mechanisms involved in these changes.4z5While information on maternal cardiac function from invasive hemodynamic monitoring is widely acknowledged to be the most reliable, echocardiography more readily lends itself to longitudinal studies appropriate for investigation of serial changes in pregnanCY.6-8 Cardiac output is increased in normal pregnancy by a combination of factors, including increased preload, decreased afterload, increased compliance of the conduit vessels,ventricular remodeling, and changesin the renin-angiotensin-aldosterone system.’ Although a concomitant increase in myocardial contractility would also seemto contribute to this increased cardiac output, this has not been demonstrated conclusively.’ The objectives of the present investigation were 1) to evaluate prospectively the changes in the hemodynamits, ventricular remodeling, and ventricular contractility of normal primigravid pregnant women, and 2) to further explore the mechanisms responsible for the cardiovascular changes unique to pregnancy.

Materials and Methods The study protocol was approved by the Human Research Review Committee of the University of New Mexico School of Medicine and all patients gave written, informed consent. The study design was longitudinal and only primigravidas were enrolled. Subjects

0029.7844/97/$17.00 PII SOO29-7844(97)00090-2

957

were recruited from the general prenatal clinic from May of 1992to May of 1995. Exclusion factors included preexisting cardiac disease, chronic hypertension, or excessive obesity (defined as a body mass index [BMI] exceeding 30.0 kg/m*). Subjects were also excluded from analysis after delivery if they had developed preeclampsia (defined as blood pressure of 140/90 mmHg or greater on at least two occasions accompanied by proteinuria of 300 mg/ 24 hours or 1+ proteinuria on dipstick) or if their postpartum baseline BMI exceeded 30.0 kg/m2. Studies were done in early (mean -Cstandard error, 15 2 0.2 weeks), mid (26 2 0.1 weeks), and late (36 2 0.1 weeks) gestation, as well as postpartum (6 t 0.1 weeks). All echocardiographic examinations and measurements were done by the same technician to assure accuracy and consistency. At least five measurements of each index were made and the closest three averaged and reported. All measurements were performed with the subjects in the left lateral recumbent position with the head of the bed elevated 15 degreesand after the subjectshad rested for at least 15 minutes. No measurementswere carried out in the presence of uterine contractions, and no subjects were receiving any medications other than prenatal supplemental iron, calcium, and vitamins. All studies were performed with either a Hewlett-Packard 500 (Glendale, AZ) or Acuson 120XP (Mountainview, CA) ultrasound systems using either a 2.25- or 3.5-MHz transducer to obtain two-dimensional and M-mode images. Nova-Microsonic Colorview digitizer/analyzer equipment (Allendale, NJ) was used to measure left ventricular volumes. Studies were videotaped and subsequently analyzed off-line. Standard two-dimensional images of the heart were obtained in the parasternal, apical, and subcostalwindows and from these windows apical two- and four-chamber long-axis images of the left ventricle were used to acquire ventricular volumes and ejection fractions. At least three measurements were averaged to report the results. Heart rate (HR) was determined directly from the R-R interval of an electrocardiograph recorded simultaneously. Stroke volume was calculated by measuring the left ventricular end-diastolic and end-systolic volumes using the two-dimensional echo disk summation method (modified Simpson’s rule).” This method is based on measuring orthogonal planes from the apical two- and four-chamber views and calculating volume by summating areas of 20 cylinders or discs of equal height. Stroke volume (SV) in mL is then calculated: SV = left ventricular - left ventricular

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end-diastolic

volume

end-systolic volume

Cardiac Function in Pregnancy

and cardiac output (CO) in liters per minute is derived from the formula: CO=SVxHR Cardiac index in liters per square meter was derived by dividing cardiac output by the patients’ body surface area in meters’. Ejection fraction was calculated as end-diastolic volume minus end-systolic volume divided by end-diastolic volume X 100. Blood pressure was measured from the bra&al artery with a manual cuff and with the subject in left lateral decubitus position. The fourth Koratkoff sound was used to indicate the diastolic value, and mean arterial pressure (MAP) in mmHg was calculated by the formula: MAP = systolic blood pressure + 2(diastolic blood pressure) / 3 Total peripheral resistance (TPR) expressed as dynes/second / cm -5 was calculated from the formula: TPR = (80)MAP / CO Left ventricular (LV) mass (g) was calculated by the two-dimensional echo area-length method of Devereux et al:l’ LV mass = (1.055)(0.833)(outer

short axis area

x length + 1) - (inner short axis area x length)

M-mode echocardiography was used to make measurements employed in the calculations of indices of ventricular contractility and remodeling. These included left ventricular wall thickness, radius, and the dimensions used in the calculations of fractional shortening, velocity of circumferential fiber shortening (vcf,), wall stress (a,,), and left ventricular mass.The recommendations of the American Society of Echocardiography were used.” The M-mode of the left ventricle was obtained from the short-axis two-dimensional image, with the M-mode cursor bisecting the ventricle just below the tips of the mitral valve leaflets and angled downward to the level of the papillary muscles. End diastole was defined as the onset of the Q wave of the electrocardiogram and end systole asthe nadir of septal motion, both averaged over five cardiac cycles. Fractional shortening (FS%) was calculated as enddiastolic dimension minus end-systolic dimension divided by end-diastolic dimension X 100. Left ventricular ejection time (ET,) was calculated from the measured excursion of the left ventricular posterior wall during systole and was rate-corrected to a heart rate of 60 beats/min by dividing by the square root of the R-R interval. The rate-corrected mean velocity of circumferential fiber shortening (vcf,) of the left

Obstetrics 0 Gynecology

Table

ventricle (in cm/second) was calculated and normalized to the end-diastolic dimension by dividing fractional shortening by the rate-corrected ejection time:

Age(Y) Gestation at delivery (wk) Weight at 6 weeks postpartum Body surface area at 6 weeks Body mass index (kg/m’) Ethnicity (%) Hispanic Non-Hispanic white Other*

vcf, = FS% / ET/ (R-R)“* The left ventricular meridional end-systolic wall stress (a,, in g/cm’) was calculated by the method of Grossman et al”: SBP x LVESD x 1.35 Uees= 4(LVWTS) x (1 + LVWTS/LVESD)

Mean ? standard error. *Three Native American, American.

where SBP is systolic blood pressure, LVESD is leftventricular dimension at end systole, and LVWTS is left ventricular wall thickness at end systole. The left ventricular end-systolic wall stress-velocity of circumferential fiber shortening relation, a load-independent index of myocardial contractility (u,,/vcf,) was calculated according to the method of Colan et aLI3 The radius-to-wall thickness ratio (r/h) was calculated by dividing the left ventricular end-diastolic dimension (LVEDD) by the end-diastolic posterior wall thickness measurement (left-ventricular wall thickness): r/h

(kg) postpartum

21.0 39.2 64.5 1.66 24.2

(m*)

2 0.5 k 0.2 2 1.6 3- 0.02 + 0.1

51 (67) 18 (24) 7 (9) two

African

American,

and two

Asian

estimate in order to allow for patient dropout. The variance used in the sample size calculation for cardiac output values was 2 1.0 L/minute.14

Results Eighty-nine women completed all four studies, of whom four developed preeclampsia and nine had baseline postpartum BMIs exceeding 30.0 kg/m’. These subjectswere not included in the final analysis, leaving 76 women for analysis. The demographic characteristics of these women are summarized in Table 1. In all subjects, the left ventricle was noted to contract in a symmetric manner, and no subject had evidence of left ventricular hypertrophy. The hemodynamic data at early, mid, and late gestation, as well as at the postpartum baseline examination, are summarized in Table 2. Comparing the baseline postpartum study and those obtained in late gestation, cardiac output increased 27% (from 4.2 ? 0.1 to 5.8 f 0.2 L/minute, P = .OOl), mediated by increases in both heart rate and stroke volume, and total peripheral resistance decreased 33% (from 1356 2 69 to 941 + 37 dynes/second/ cme5, P = .OOl). Changesin the indices of ventricular remodeling over the course of pregnancy are summarized in Table 3.

= LVEDDJLVWT

Within-subjects repeated measures analysis of variance was performed for each variable, using the SAS statistical package (SAS Institute Inc., Cary, NC). Fisher’s least significant difference was used for post hoc pairwise comparisons. Significance was set at P < .05. Means and standard errors were used to describe the demographic and hemodynamic data. A power study performed before inception of the study had indicated that 14 paired data points (pairing late gestation and postpartum data) would be necessary to demonstrate with 80% power (CX = .05) a 25% difference in cardiac output, but that 57 paired data points would be necessary to demonstrate a 15% difference in myocardial contractility, between late gestation and the postpartum baseline. We tried to recruit a sample size double this Table

1. SubjectDemographics

2. HemodynamicData Early

Mid

PP

Late

P

Heart rate (bpm) Stroke volume (mL/beat) Cardiac output (L/min) Cardiac index (L / min/ m*) Mean arterial pressure (mmHg) Total peripheral resistance (dynes/set/cm-5) Mean t standard deviation. l’l’ = postpartum; P = overall significance significant difference as a post-hoc test. *P < ,001 compared to postpartum study difference as a post-hoc test.

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over

time calculated

calculated

using

using

repeated

repeated measures

measures

of analysis

of analysis

of variance

Gilson

et al

of variance and using

and using Fisher’s

Fisher’s

least

least significant

Cardiac Function in Pregnancy

959

Table

3. Indicesof Ventricular Remodeling Early

Left ventricular diastolic dimension (cm) Left ventricular diastolic volume (mL) Diameter/length ratio Left ventricular diastolic wall thickness (mm) Radius/wall thickness ratio Left ventricular mass (g) Means + standard PP = postpartum; significant difference * P < ,001 calculated + P < .05 compared as a post-hoc test.

4.52 95 0.56 75 3.1 129

k 2 k k 2 2

Mid 0.05 2 0.01 1 0.6 2

4.53 98 0.55 78 3.0 131

4. Indices

0.04 2* 0.01 2’ 0.F 3

of Ventricular

Gilson

et al

0.04 3* 0.01 2* 09 2

4.50 89 0.55 71 3.2 129

k + f k + k

0.04 2 0.01 1 0.6 3

NS ,002 NS .OOl .03 NS

0.01 to 0.31 +- 0.01 second, P = .OOl). Left-ventricular wall stress, however, demonstrated significant decreases in late gestation relative to the postpartum baseline values (36.3 -+ 1.0 to 31.9 5 1.0 g/cm*, P = .OOl). Calculating the ratio of wall stress to velocity of circumferential fiber shortening, a load-independent assessmentof left ventricular function, revealed a significant decrease because vcf, increased to a lesser extent than wall stress decreased. This implies that, independent of both the increased preload and heart rate (reflected in vcf,), as well as independent of the decreased systolic blood pressure (reflected in wall stress),intrinsic myocardial contractility was enhanced. Discussion This longitudinal prospective study of cardiovascular changes in normal pregnancy demonstrated that left ventricular function is enhanced as a result of a combination of increased preload, decreasedafterload, and an increase in intrinsic myocardial contractility that is independent of loading conditions. While confirming many earlier findings, the current investigation also produced important new information. We presented evidence that modestly enhanced intrinsic myocardial

Mid

Early

960

k 5 + + + -t

P

Contractilitv

Ejection fraction (%) Fractional shortening (%) Velocity of circumferential fiber shortening Ejection time (second), rate corrected Left ventricular wall stress (g/cm’) uJvcf, ratio Means + standard PP = postpartum; significant difference * P < ,001 calculated ’ P C .05 compared as a post-hoc test.

4.52 99 0.55 78 3.0 135

PP

error. P = overall significance over time calculated using repeated measures of analysis of variance and using Fisher’s least as a post-hoc test. using repeated measures of analysis of variance and using Fisher’s least significant difference as a post-hoc test. to postpartum study calculated using repeated measures of analysis of variance and using Fisher’s least significant difference

There was a significant increase in left ventricular end-diastolic dimension over the course of gestation compared with baseline (from 89 + 2 to 99 ? 3 mm, P = .002). The ventricular diameter to length ratio did not change, implying no eccentric dilation. Left-ventricular posterior wall thickness in diastole also increased over time (from 71 -C 1 to 78 ? 2 mm, P = .OOl). The radius-to-wall thickness ratio demonstrated a decrease in late gestation relative to the postpartum study. Wall thickness increased to a greater degree than diastolic internal dimension, implying a greater degree of concentric ventricular “hypertrophy” than spherical ventricular dilation. Concomitantly, there was a small, but not significant, increase in left ventricular mass (from 129 % 3 to 135 ? 2 g, P = .08), over the course of pregnancy. Gestational changes in indices of ventricular contractility are presented in Table 4. Although stroke volume definitely increased over the course of gestation, neither ejection fraction nor resting fractional shortening changed significantly. As a result, there was a slight but insignificant increase in the velocity of circumferential fiber shortening (from 1.25 ? 0.02 to 1.27 ? 0.02 cm/second, P = .47), although there was a significant decreasein the rate corrected ejection time (from 0.34 +

Table

2 2 + + 2 +

Late

(cm/second)

70 + 44kl 1.23 + 0.32 + 25.5 ? 21.5 T

1 0.02 0.01 0.7 0.8

70 45 1.29 0.30 23.9 19.4

2 2 ? T ? 2

Late 1 1 0.02 0.01* ox+ 0.9+

71 45 1.27 0.31 23.6 19.4

+ 1 k 1 5 0.02 2 0.01* I!Y0.7* I!Y0.8+

PP 70 5 4451 1.25 C 0.34 2 26.9 2 22.2 2

P 1 0.02 0.01 0.8 0.9

NS NS NS ,001 ,001 .Ol

error. P = overall significance over time calculated using repeated measures of analysis of variance and using Fisher’s least as a post-hoc test; eeS = end systolic wall stress; vcfc = velocity of circumferential fiber shortening. using repeated measures of analysis of variance and using Fisher’s least significant difference as a post-hoc test. to postpartum study calculated using repeated measures of analysis of variance and using Fisher’s least significant difference

Cardiac Function in Pregnancy

Obstetrics & Gynecology

contractility contributes to the overall increase in cardiac output seen in normal pregnancy. Comparison of our findings with those of other longitudinal studies of cardiovascular physiology in normal pregnancy, using both noninvasive3’4,‘4 and invasive2,r5 techniques, demonstrates the reliability of our methodology. We did not see quite as large a percentage change in cardiac output as some other studies, which may be due to the fact that our baseline control study was, for logistic reasons, carried out at 6 weeks postpartum. As noted by others,‘6*” this time frame may not be sufficiently remote from the pregnancy to reflect baseline hemodynamic conditions accurately. We used the disk summation method (modified Simpson rule), ‘” in which stroke volume is determined as the difference between the manually planimetered, computer-calculated end-diastolic volume and the end-systolic volume, and cardiac output and ejection fraction are calculated using this value. As noted by Rokey et al,” potential problems with calculations using two-dimensional techniques are that they rely heavily on computational assistance, and dropout of echoes may interfere with planimetry of the entire ventricle. With these caveats in mind, we, nevertheless, believe that our technique has been repeatedly validated, is widely accepted, is associated with an acceptably low variability of measurement, and compares favorably with alternate techniques such as pulsed Doppler echocardiography. The disk method has likewise shown excellent correlation to angiographic studies in nonpregnant subjects.” Colan et alI3 have pointed out that ejection phase indices of myocardial performance have limited usefulness in predicting alterations in intrinsic contractility because of their dependence on left-ventricular loading conditions. The rate-corrected vcfc, which incorporates end-diastolic dimension as well as ventricular ejection time, is a preload-independent index of ventricular function. Left ventricular a,, on the other hand, reflects the combined effects of peripheral vascular resistance as well as factors intrinsic to the heart (ventricular wall thickness, dimension, and chamber pressure) and is independent of afterload.‘O The a,,/vcf, ratio then becomes an index of myocardial function that is load independent and contractility sensitive. During mid and late pregnancy in this study, there was a small and statistically insignificant shortening of vcfc, but a 12% decrease in wall stress compared to the postpartum study. The uees/ vcf, ratio concomitantly decreased 13%, implying a significant (P = .Ol) increase in intrinsic myocardial contractility in pregnancy that is independent of loading conditions. Somewhat unexpectedly, we did not find evidence of spherical dilatation in late gestation relative to the

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postpartum baseline study. The slight and insignificant change in left ventricular mass argues against an improvement in the overall efficiency of myocardial performance solely on the basis of ventricular hypertrophy. Normal pregnancy results in a diminution of left ventricular afterload and concomitant increases in preload with enhancement of cardiac output. Other factors that help effect this dramatic change include an increase in the compliance of the conduit vessels, increase in heart rate, alterations in the renin-angiotensin system, ventricular remodeling, and, it seems intuitive, increase in intrinsic myocardial contractility. Although previous investigators4s2’ have not been able to demonstrate enhanced contractility separate from altered loading conditions, we believe that, by examining the uees/vcf, relationship in a longitudinal fashion over time, we were able to demonstrate this clearly. Animal studies, while not demonstrating obvious changes in myocardial cytomorphometry,** do demonstrate increases in myosin enzymology accompanying improved contractile performance during pregnancy23 and lend support to this idea. The factors responsible for this increase in contractility in human pregnancy remain to be elucidated and would be an important subject for further research.

References 1. Ueland

2.

3.

4.

5.

6.

7.

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K, Novy MJ, Peterson EH, Metcalfe J. Maternal cardiovascular dynamics. IV. The influence of gestational age on maternal cardiovascular response to posture and exercise. Am J Obstet Gynecol 1969;104:856-64. Bader RA, Bader ME, Rose DJ, Braunwald E. Hemodynamics at rest and during exercise in normal pregnancy as studied by cardiac catheterization. Eur J Clin Invest 1955;34:1524-36. Robson SC, Hunter 5, Boys RJ, Dunlop W. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 1989;256:H7060-5. Katz R, Karliner JS, Resnik R. Effects of a natural volume overload state (pregnancy) on left ventricular performance in normal human subjects. Circulation 1978;58:434-41. Mashini IS, Albazzaz SJ, Fade1 HE, Abdulla AM, Hadi HA, Harp R, et al. Serial noninvasive evaluation of cardiovascular hemodynamits during pregnancy. Am J Obstet Gynecol 1987;156:1208-13. Lee W, Rekey R, Cotton DB. Nonmvasive maternal stroke volume and cardiac output determinations by pulsed Doppler echocardiography. Am J Obstet Gynecol 1988;138:505-10, Belfort MA, Rokey R, Saade GR, Moise KJ. Rapid echocardiographic assessment of left and right heart hemodynamics in critically ill obstetric patients. Am J Obstet Gynecol 1994;171:88492. Easterling TR, Watts DH, Schmucker BC, Benedetti TJ. Measurement of cardiac output during pregnancy: Validation of Doppler technique and clinical observations in preeclampsia. Obstet Gynecol 1987;69:845-50. Gilson GJ, Masher MD, Conrad KP. Systemic hemodynamics and oxygen transport during pregnancy in chronically instrumented, conscious rats. Am J Physiol 1992;263:H1911-8. American Society of Echocardiography Committee on Standards,

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Address

reprint

requests

to:

George J. Gilson, MD Department of Obstetrics and Gynecology University of New Mexico Hospital 2211 Lomas NE Albuquerque, NM 87131

Received October 3, 1996. Received in revised form December Accepted ]anuary 23, 1997.

19, 1996.

Copyright 0 1997 by The American College of Obstetricians Gynecologists. Published by Elsevier Science Inc.

Obstetrics

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6 Gynecolo;yy