Maternal Cardiac Dysfunction and Remodeling in Women With Preeclampsia at Term

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DOI: 10.1161/HYPERTENSIONAHA.110.162321 published online Nov 22, 2010; Hypertension

Basky Thilaganathan Karen Melchiorre, George Ross Sutherland, Aigul Baltabaeva, Marco Liberati and

TermMaternal Cardiac Dysfunction and Remodeling in Women With Preeclampsia at

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Maternal Cardiac Dysfunction and Remodeling in WomenWith Preeclampsia at Term

Karen Melchiorre, George Ross Sutherland, Aigul Baltabaeva, Marco Liberati, Basky Thilaganathan

Abstract—Preeclampsia is a disease associated with significant cardiovascular morbidity during pregnancy and in later life.This study was designed to evaluate cardiac function and remodeling in preeclampsia occurring at term. This was aprospective case–control study of 50 term preeclampsia and 50 normal pregnancies assessed by echocardiography andtissue Doppler analysis. Global diastolic dysfunction was observed more frequently in preeclampsia versus controlpregnancies (40% versus 14%, P�0.007). Increased cardiac work and left ventricular mass indices suggest that leftventricular remodeling was an adaptive response to maintain myocardial contractility with preeclampsia at term.Approximately 20% of patients with preeclampsia at term have more evident myocardial damage. Diastolic dysfunctionusually precedes systolic dysfunction in the evolution of ischemic or hypertensive cardiac diseases and is of prognosticvalue in the prediction of long-term cardiovascular morbidity. The study findings also have significant implications forthe acute medical management of preeclampsia. (Hypertension. 2011;57:00-00.) ● Online Data Supplement

Key Words: diastolic dysfunction � echocardiography � left ventricular remodeling � preeclampsia � pregnancy� strain rate � tissue Doppler

Preeclampsia (PE) is a pregnancy complication of placen-tal etiology with acute onset of predominantly cardiovas-

cular manifestations.1 The pathological changes in this disor-der are primarily ischemic in nature and are known to affectthe placenta, kidney, liver, and brain, whereas there is scantand conflicting information about the impact on the heart.1–7

Cardiopulmonary morbidity is seen in a significant propor-tion of preeclamptic cases8 and autopsy data have demon-strated that preeclamptic women have a 10-fold higherprevalence of myocardial contraction band necrosis thandeaths in pregnancy from other causes.9 Epidemiological datahave also highlighted the strong relationship between pre-eclampsia and premature morbidity and mortality from car-diovascular disease10,11 thought to be related to shared car-diovascular risk factors.12 All these data suggest thatpreeclampsia may be associated with the potential for signif-icant myocardial damage. Tissue Doppler (TD) velocity anddeformation indices are highly sensitive at detecting evenmild myocardial damage.13–18 The aim of this study is to testthe hypothesis that PE provokes significant myocardial dam-age/dysfunction by using both conventional echocardiogra-phy and TD analysis in women with and without PE.

MethodsStudy SubjectsThis was a prospective case–control study carried out over a 2-yearperiod from January 2008. All women with singleton pregnancy and

PE at term (37 to 42 completed weeks of gestation) were recruitedconsecutively as cases after informed consent and with local insti-tutional review committee approval. Only women without comor-bidities, nonsmokers, and before starting any medication were askedto take part in the study. PE and nonproteinuric gestational hyper-tension (GH) were defined according to the International Society forthe Study of Hypertension in Pregnancy guidelines.19 Normotensivehealthy, nonsmoking control subjects matched for maternal age,gestation, and ethnicity and women diagnosed with GH at term werealso recruited as control subjects from the routine antenatal clinic.

EchocardiographyAll subjects were studied by standard 2-dimensional and Dopplertransthoracic echocardiography at rest. Patients were studied in theleft lateral decubitus position and data acquired at end expirationfrom standard parasternal/apical views using a GE Vivid 9 scan-ner.20,21 For each acquisition, 3 cardiac cycles of noncompresseddata were stored in cine-loop format and analyzed without blindingoffline by 1 investigator (K.M.). Cardiac indices were normalized forbody surface area, height, and end-diastolic left ventricle long orshort axis lengths, as appropriate.22–24 TD, strain, and strain rateindices are given as absolute values.

Heart RemodelingChamber quantification and left ventricular (LV) geometric patternwere estimated using M-mode as previously described.20 Proximalseptal bulging was assessed in the parasternal long-axis and apical4-chamber views.25

Systolic FunctionLV volumes and ejection fraction were derived from Simpson’smodified biplane method from apical 4-chamber and 2-chamber

Received September 2, 2010; first decision September 25, 2010; accepted October 25, 2010.From the Fetal Maternal Medicine Unit (K.M., B.T.), Department of Obstetrics and Gynecology and the Department of Cardiology and Cardiothoracic

Surgery (K.M., G.R.S., A.B.), St Georges Hospital, University of London, London, UK; and the Department of Obstetrics and Gynecology (K.M., M.L.),University of Chieti, Chieti, Italy.

This study was approved by the Wandsworth Local Research Ethics Committee (Ref No. 01.78.5).Correspondence to Basky Thilaganathan, Fetal Maternal Medicine Unit, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK.

E-mail [email protected]© 2010 American Heart Association, Inc.

Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.110.162321

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views.20 Maternal blood pressure was measured following therecommendation of the National High Blood Pressure EducationProgram Working Group on High Blood Pressure in Pregnancy.1

Hemodynamic and systolic cardiac indices were calculated asdescribed before26 (see supplementary material; available at http://hyper.ahajournals.org). Longitudinal and radial systolic functionwere assessed both globally and regionally using color and pulsedTD velocity indices and color TD-encoded strain and strain rateindices as previously described.17,18

Diastolic FunctionGlobal diastolic dysfunction was graded using a diagnostic algorithm(Figure 1) based on the recommendations of European Associationof Echocardiography and American Society of Echocardiography21

with the following adjustments: (1) age is a primary factor indefining normal velocity and time interval indices.21 Indices wereonly considered as abnormal if they were �2 SDs from the expectedmean for the age group; (2) circulating volume in pregnancy isincreased.1 Emphasis was therefore given to those cardiac indicesthat are least affected by loading conditions (left more than septalmitral annulus TD indices)23; and (3) the acute nature of PE on apreviously normal cardiovascular system.1 Specific importance wasgiven to indices that reflect diastolic function at the time ofassessment (transmitral, pulmonary and TD velocities, time inter-

vals, and regional deformations) rather than indices of left atrialremodeling, which commonly reflect the cumulative effect of fillingpressure in chronic conditions such as longstanding essentialhypertension.21

Regional longitudinal diastolic function was assessed by measur-ing color TD early and late diastolic velocity and strain rate indicespositioning the sample at the level of the basal and midsegments ofthe inferoseptal and anterolateral LV walls in 4-chamber view.Early/late diastolic myocardial TD index ratio of �1 was taken as anindex of altered segmental relaxation (segmental diastolic dysfunc-tion) as previously proposed.27,28

Statistical AnalysisData were analyzed using SPSS 12 software (SPSS, Chicago, Ill).Variables were compared using Mann-Whitney U or �2 tests, asappropriate. Paired group comparisons were only undertaken ifKruskal-Wallis testing indicated significant differences. A samplesize of 22 in each group was calculated to observe a �20%difference in early diastolic mitral wave velocity/average lateral andseptal diastolic myocardial velocities ratio between cases and controlsubjects with 85% power and a 5% Type I risk.29 Stepwise multipleregression analysis was used to assess the influence of cardiacparameters, demographic variables (ethnicity, maternal age, bodymass index), and pregnancy characteristics on indices of cardiac

Normal diastolic function

E/A<0.73 DT>194 ms IVRT>83 ms

Val ∆ E/A<0.5 ±Av E/E1<=8

E/A: 0.73-2.33 DT: 138-194 ms IVRT: 51-83 ms ±AR-A>=30 ms ±Val ∆ E/A>0.5 ±Av E/E1: 9-12

E/A>2.33 DT<138ms

IVRT<51 ms ±AR-A>=30 ms ±Val ∆ E/A>0.5 ±Av E/E1>=13

Impaired myocardial relaxation with normal

left ventricular end diastolic pressure

(GRADE I)

Impaired myocardial relaxation with increased left

ventricular end diastolic pressure

(GRADE Ia)

Lateral E1 >=14 cm/sec

Lateral E1<14 cm/sec

ARdur-Adur<30 ms ARdur-Adur>=30 ms

ARdur-Adur Pseudonormal filling pattern

(GRADE II)

Restrictive pattern (GRADE III)

EF>50%

Figure 1. Diagnostic algorithm for the classification of diastolic dysfunction. EF indicates ejection fraction; Lateral E1, pulsed wave tis-sue Doppler peak early diastolic velocity at the left side of mitral valve annulus; E, peak early diastole transmitral wave velocity; A, peaklate diastole transmitral wave velocity; E/A, early to late diastole peak transmitral velocity ratio; DT, deceleration time of E wave; IVRT,isovolumetric relaxation time; Adur, mitral A wave duration; Val � E/A, percentage of decrease in the mitral E/A ratio with Valsalvamaneuver; Av E/E1, E to average of lateral and septal E1 velocities; AR, peak retrograde late diastolic pulmonary wave velocity; ARdur,AR duration.

2 Hypertension January 2011



function and remodeling. A value of P�0.05 was consideredstatistically significant and all tests were 2-sided. To test interob-server and intraobserver reproducibility, 2 independent operators(K.M. and A.B.) undertook offline analyses on the cine loops from10 randomly selected women and repeated this after 1 month. The95% limits of agreement, coefficients of variation, within-subjectSDs, and repeatability coefficients were calculated.

ResultsA total of 50 women with PE and 50 women with normalpregnancy were recruited during the study period. Thesecases were closely matched (Table 1) for age, ethnicity, andgestational age.

Diastolic FunctionTwenty women with PE (40%) met the criteria for the diagnosisof global diastolic dysfunction compared with 7 (14%) in thecontrol group (P�0.007; Table 2; Figures 2 and 3). In thewomen with PE, there were 13 with Grade I, 4 with Grade Ia,and 3 with Grade II diastolic dysfunction. PE cases with normalglobal diastolic function still had evidence of regional diastolicdysfunction compared with control subjects (Table 3; Figure 4).PE women with global diastolic dysfunction had significantlyhigher end-systolic left atrial volume index than control subjectswith 12 women having a left atrial volume index above thecutoff value of 34 mL/m2 (Table 2). The only demographicdifference was that PE women with global diastolic dysfunctionwere significantly older than those without.

Remodeling and HemodynamicPE women had significantly higher LV mass and cardiac workindices compared with control subjects with no significantdifference in LV end-systolic wall stress index (Table 4). PEwomen with global diastolic dysfunction, but not those withnormal global diastolic function, had significantly higher totalvascular resistance index compared with control subjects (Table4). The proportion of patients with LV geometric remodelingwas significantly higher in the PE group (36 of 50 [72%]) versusthe control group (12 of 50 [24%]; P�0.0001; Table 4; Figure5). There were 10 cases of LV concentric hypertrophy amongpatients with PE. LV remodeling was asymmetrical with thepresence of basal septal bulge seen (n�7) only in the womenwith PE with global diastolic dysfunction (P�0.001).

Systolic FunctionThere were no significant differences in indices of global (radialand longitudinal) systolic function between the groups both byconventional and TD assessment. Regional systolic function wasalso similar between PE with normal global diastolic functionand control subjects. PE women with global diastolic dysfunc-tion had significantly reduced regional (basal septal) end-systolicstrain and peak-systolic strain rate indices compared with controlsubjects. The amplitude of basal septal postsystolic shorteningindex was well above 25% in 5 of 20 (25%) PE women withglobal diastolic dysfunction compared with none of the controlsubjects (P�0.002; Figure 6).

Interdependency of IndicesMultiple regression analysis showed that hemodynamic indi-ces were the only independent predictors of LV mass indices(R�0.50; P�0.0001). Hemodynamic and LV remodelingindices were independent predictors of global diastolic func-tion. TD indices of myocardial relaxation and filling pres-sures appeared to be independently determined by afterload,longitudinal systolic function, and LV mass indices. Therewas a strong and independent relationship between longitu-dinal systolic and diastolic functional indices. Demographicand pregnancy characteristics did not independently contrib-ute to echocardiographic findings.

Gestational HypertensionWomen with GH (n�20) who were also matched for age,gestation, and ethnicity, demonstrated equivalent changes inLV geometry/remodeling to women with PE but did not haveany evidence of significant global diastolic or systolic dys-function (Table 5).

Repeatability and ReproducibilityThe intraobserver and interobserver coefficients of variationranged between 1.7% and 12%. The intra- and interobserveragreements were good for all indices. Please refer also to listof supplementary material.

DiscussionThe study data indicate that most women with PE undergoadaptive responses with significant heart remodeling, but asubgroup of approximately 20% of women demonstrate moreevident myocardial damage and overt global diastolic dysfunction.

Table 1. Demographic Characteristics and PregnancyOutcome of Cases With Preeclampsia and Control Subjects*

Control Subjects(n�50)

Cases(n�50) P

Recruitment

Maternal age, years 31.5 (26–36) 32.0 (29–37) 0.6

Nulliparous 32 (64) 34 (68) 0.8

White 32 (64) 32 (64) 0.9

Afro-Caribbean 11 (22) 11 (22) 0.8

Asian 7 (14) 7 (14) 0.8

Prepregnancy BMI, kg/m2 23.9 (21.2–27.5) 25.9 (24.1–31.1) 0.0001

Prepregnancy BSA, m2 1.5 (1.3–1.8) 1.8 (1.4–2.1) 0.1

SBP at booking visit,mm Hg

120 (110–125) 120 (110–130) 0.5

DBP at booking visit,mm Hg

60 (60–70) 60 (60–70) 0.2

Assessment

BMI, kg/m2, atassessment

27.7 (24.4–33.1) 30.1 (27.9–35.8) 0.005

BSA at assessment, m2 1.7 (1.5–2.1) 2.1 (1.7–2.5) 0.024

Gestational age atassessment, weeks

37 (37.2–38.5) 37 (37.5–39) 0.1

SBP at assessment,mm Hg

110 (100–120) 150 (140–160) 0.0001

DBP at assessment,mm Hg

70 (60–80) 95 (90–100) 0.0001

*Values are given as median (interquartile range) or no. of subjects(percentage).

BMI indicates body mass index; BSA, body surface area; SBP, systolic bloodpressure; DBP, diastolic blood pressure.

Melchiorre et al Cardiac Impairment in Preeclampsia at Term 3



Diastolic FunctionThis is the first study to use an evidence-based algorithm21 todiagnose and grade diastolic dysfunction in women pres-enting with PE. This global approach to the interpretation ofcardiac indices demonstrates impaired myocardial relaxationand normal global systolic function in almost half of the

women with PE. Studies in patients with ischemic andhypertensive cardiac disorders have also demonstrated simi-lar findings, termed “isolated diastolic dysfunction.”30 Previ-ous studies of cardiac function and remodeling in PE havefailed to identify a consistent pattern of diastolic dysfunctionpossibly due to the inadequacy of the conventional cardiac

S1S1S1

1 E1 E1

A1

E

A1 A1

15

10

5

-5

5

-10

-15

10-.16

-2.0 -1.5 -1.0 -0.5 0.087HR100 mm/s

[cm/s]

.16

Figure 2. Pulsed wave tissue Doppler imagingmyocardial velocity profile recorded at the septalsite of mitral valve annulus. Reduced peak systolic(S1) and early diastolic myocardial velocity (E1) andincreased late diastolic myocardial velocity (A1)with E1/A1 ratio �1.

Table 2. Global Diastolic Function in Cases Versus Control Subjects*

ParametersControl Subjects

(n�50)

Cases With NormalDiastolic Function

(n�30)

Cases With GlobalDiastolic Dysfunction

(n�20)

Control SubjectsVersus Cases With

Normal Diastolic Function(P Values)


Diastolic Dysfunction(P Values)

Left atrial remodeling

LAVI, mL/m2 28.5 (19.9–35) 27 (25–33) 40 (30–42) 0.7 0.005

Mitral inflow

E/A ratio 1.14 (0.88–1.43) 1.34 (1.27–1.55) 0.81 (0.73–0.95) 0.06 0.0001

DT, ms 169 (150–200) 199 (154–218) 207 (191–229) 0.4 0.0001

IVRT, ms 83.5 (71.5–96.8) 95.5 (92.5–99.3) 96 (91–101) 0.9 0.0001

Pulmonary venous flow

S/D ratio 1.1 (0.90–1.30) 1 (0.81–1.23) 1.4 (1.2–1.5) 0.2 0.04

ARdur–Adur, ms 0 (�16.3–24.5) 6 (�22.5–31) 14 (�6–31) 0.04 0.06

ARdur–Adur �30 ms 5 (10) 8 (27) 6 (30) 0.1 0.03

Mitral annular motion

Septal E1, cm/sec 10 (8.3–13) 12 (11.2–13) 6 (6–9) 0.1 0.001

Septal E1/A1 ratio 1.13 (0.90–1.36) 1.47 (1.19–1.93) 0.75 (0.63–0.86) 0.08 0.0001

Lateral E1, cm/sec 13 (12–16) 13 (11–17) 10 (8–13) 0.9 0.001

Lateral E1/A1 ratio 1.6 (1.3–1.9) 1.7 (1.3–2.5) 0.83 (0.60–1.1) 0.7 0.0001

Left atrial and ventricularfilling pressure

Septal E/E1 ratio 7 (6.1–8.4) 6.8 (6.2–8) 9.5 (7.3–11.3) 0.9 0.001

Lateral E/E1 ratio 5.1 (4.6–6.3) 6 (5.6–7.5) 6.3 (5.1–7.7) 0.1 0.007

Average E/E1 ratio 6.1 (5.2–6.5) 6.5 (6.3–6.9) 7.9 (6–8.3) 0.1 0.004

*Values are given as either median (interquartile) or no. of subjects (percentage).LAVI indicates left atrial volume index (LAV/BSA); E, peak early diastole transmitral wave velocity; A, peak late diastole transmitral wave velocity; DT, deceleration

time of E wave; IVRT, isovolumetric relaxation time; S, peak systolic pulmonary venous flow velocity; D, peak anterograde early diastolic pulmonary venous flowvelocity; AR, peak retrograde late diastolic pulmonary venous flow velocity; ARdur, AR duration; (ARdur–Adur), the time difference between pulmonary AR-waveduration and mitral A-wave duration; E1, peak early diastolic velocity at mitral valve annulus; A1, peak late diastolic velocity at the mitral valve annulus; average E/E1ratio, E to average of lateral and septal E1 velocities.




indices used.3,4 The current study used color and pulsed TDvelocity and deformation indices, which are well correlatedwith invasive indices of myocardial relaxation/filling pres-sures and long-term cardiovascular risk.31–33 Furthermore,previous studies disregarded the interdependency of cardiacevents by assessing differences in cardiac indices in isola-tion,3–6 but rather evaluating global diastolic and systolicindices using a validated diagnostic algorithm. LV myocar-dial relaxation is paradoxically an energy-dependent processthat results in a rapid decrease in LV pressure after the end ofcontraction and during early diastole.21 Hence, the process ofmyocardial relaxation is more vulnerable than contractionand is apparently compromised in both early-stage cardiovas-cular disorders30 and in PE. Multiple regression analysisdemonstrated that in PE, diastolic dysfunction was signifi-cantly related to both increased afterload and/or increased LVmass as seen in nonpregnant subjects.32,33 Longitudinal sys-

tolic and diastolic function indices were also independentlyrelated, highlighting the importance of simultaneously assess-ing systolic/diastolic function and remodeling and their syn-ergic contribution toward altered cardiac function. Womenwith PE and normal global diastolic function also hadregional diastolic abnormalities more often than controlpregnancies. These findings suggest that regional diastolicdysfunction may be an antecedent event, leading to globaldiastolic dysfunction as additional segments become affected.It is possible that women with PE and regional diastolicdysfunction may have developed global dysfunction if thepregnancy had not been delivered.

Systolic Function and Heart RemodelingGlobal (radial and longitudinal) systolic function was pre-served in women with PE. The majority of women with PEshowed evidence of LV concentric remodeling and increased

Sm Sm SmSm

Em Em Em

Am Am Am

15

10

5

15

10

5

24

-24

cm/s

10

5

0

-5

-100.0 0.5 1.0 1.5

v7.49 cm/s t1.337 sv(cm/s) 5.48

AVO AVC AVO AVC AVO AVC AVO

87HR

Figure 3. Color-encoded tissue Doppler imagingmyocardial velocity profile recorded at the basalinferoseptal segment. Reduced peak systolic (Sm)and early diastolic myocardial velocity (Em) andincreased late diastolic myocardial velocity (Am)with Em/Am ratio �1. AVO and AVC denote aorticvalve opening and closure, respectively.

Table 3. Regional Diastolic Function Color Doppler Myocardial Velocities and Deformations of Preeclamptic Women With andWithout Global Diastolic Dysfunction and Control Subjects*

ParameterControl Subjects

(n�50)

Cases With NormalDiastolic Function

(n�30)

Cases With GlobalDiastolic Dysfunction

(n�20)

Control SubjectsVersus Cases WithNormal Diastolic

Function (P Values)



Inferoseptal wall

Basal Em/Am ratio 1.6 (1.3–2.5) 2.1 (1.2–2.5) 1 (0.6–1.2) 0.9 0.0001

Mid Em/Am ratio 1.8 (1.3–2.2) 2.2 (1.1–3.4) 0.9 (0.6–1.1) 0.6 0.0001

Basal SRE/SRA ratio �1 7 (14) 8 (27) 12 (60) 0.1 0.0001

Mid-SRE/SRA ratio �1 16 (32) 13 (43) 12 (60) 0.8 0.06

Anterolateral wall

Basal Em/Am ratio 2.8 (1.6–4.5) 1.7 (1.2–5.1) 1.5 (0.9–2.4) 0.5 0.003

Mid-Em/Am ratio 2.7 (1.5–4.2) 3.3 (1.5–4.2) 1.4 (0.6–2.3) 0.8 0.013

Basal SRE/SRA ratio �1 8 (16) 10 (33) 10 (50) 0.1 0.008

Mid-SRE/SRA ratio �1 7 (14) 5 (17) 7 (35) 1 0.09

Total no. of strain rate alteredsegmental myocardial relaxation

38/200 (19) 36/120 (30) 41/80 (51) 0.034 0.0001

*Values are given as median (interquartile) or no. of subjects (percentage).Em indicates peak early diastolic myocardial velocity; Am, peak late diastolic myocardial velocity; SRE, early diastolic myocardial strain rate; SRA, late diastolic

myocardial strain rate.




LV mass indices. These changes are likely to be an adaptiveresponse to reduce the wall stress associated with increasedafterload, thereby maintaining the balance between myocar-dial oxygen demand and supply. This inference is supportedby the finding that the LV end-systolic wall stress indexbetween PE and controls remains unchanged. Multiple re-gression analysis demonstrated strong independent associa-tions between LV mass indices and hemodynamic indices.These associations are consistent with a mechanically appro-priate response to increased afterload, thus preserving intrin-

sic myocardial contractility in PE. These assertions aresupported by the findings of other studies, which also showedthat the ratio between LV mass and cardiac work indices isunchanged in PE.3,7

LV concentric hypertrophy with a characteristic basalseptal bulge and markedly reduced regional (basal septal)longitudinal systolic function with high-amplitude postsystol-ic shortening was evident in approximately 20% of womenwith PE, who also demonstrated global diastolic dysfunction.These findings suggest that there is early myocardial impair-

SRE

SRA

SRESRE

SRA SRA

SRE SRE

PSSR PSSR PSSR

AVO AVC AVO AVC AVO AVC

10

5

10

5

1.5

1.0

0.5

0.0

-0.5

-1.0

-1.50.0 0.5 1.0 1.5

3.0 1/s

-3.0 1/s

1/s SR -1.02 1/s t 1.25 s

85HR

Figure 4. Color-encoded tissue Doppler longitudi-nal strain rate curve recorded at the basal infero-septal segment. Reduced myocardial lengtheningduring passive filling (SRE) and increased myocar-dial lengthening during atrial contraction (SRA) witha SRE/SRA ratio �1. AVO and AVC denote aorticvalve opening and closure, respectively.

Table 4. Hemodynamic and Remodeling Parameters of Cases With and Without Global Diastolic Dysfunction and Control Subjects*

ParameterControl Subjects

(n�50)

PE With NormalGlobal Diastolic Function

(n�30)

PE With GlobalDiastolic Dysfunction

(n�20)

Control SubjectsVersus Cases WithNormal Diastolic

Function (P Values)



Hemodynamic indices

HR, beats/min 82 (74.5–93) 80 (72–85) 83 (74–95) 0.4 0.6

MAP, mm Hg 83 (74–92) 112 (107–117) 112 (107–120) 0.0001 0.0001

CI, L/min/m2 3.2 (2.2–3.9) 3.2 (1.9–3.9) 2.9 (2.1–3.6) 0.3 0.7

SVI, mL/m2 39 (31–48) 36 (27–44) 38 (26–40) 0.8 0.8

TVRI, (dynes�s�1�cm�5)/m2 698 (577–876) 856 (583–1083) 922 (740–1105) 0.060 0.010

Left ventricle remodeling indices

RWT 0.34 (0.29–0.41) 0.44 (0.39–0.51) 0.43 (0.41–0.50) 0.0001 0.0001

LVMI, g/m2 70 (55–82) 73 (59–93) 80 (71–92) 0.028 0.0001

Cardiac work and wall stress indices

Meridian end systolic wall stress index,dyne/cm2/m2

43 (27–48) 42 (32–52) 52 (34–63) 0.9 0.3

Cardiac work index,mm Hg�L�min�1�m�2

262 (194–291) 312 (256–401) 360 (293–412) 0.0001 0.0001

Left ventricle geometric pattern

Normal 38 (76) 12 (40) 2 (10) 0.003 0.0001

LV concentric remodeling 11 16 8 0.009 0.2

LV eccentric remodeling 1 2 0 0.6 0.6

LV concentric hypertrophy 0 0 10 … 0.0001

*Values are given as median (interquartile) or no. of subjects (percentage).HR indicates heart rate; MAP, mean arterial pressure; CI, cardiac index; SVI, stroke volume index; TVRI, total vascular resistance index; LV, left ventricle; RWT,

relative wall thickness; LVM, left ventricular mass; LVMI, left ventricular mass index normalized for body surface area (BSA).




ment, mainly localized at the level of the basal septum, inthese cases. The basal septum has the highest radius ofcurvature in the LV and is, hence, under higher local wallstress.14 The latter is usually compensated for by transseptalpressure from the right ventricle that acts to reduce wallstress.14,34 When this compensation becomes insufficient,local stress increases, leading to the development of thecharacteristic basal septal bulge and regional longitudinaldysfunction.14,25,34,35 LV concentric hypertrophy is known tobe accompanied by subendocardial fibrosis both in hyperten-sive subjects and from autopsy data.36,37 The coexistence ofLV hypertrophy and regional longitudinal systolic dysfunc-tion in PE suggests that there is regional subendocardialimpairment, presumably due to subendocardial ischemiaand/or fibrosis in the longitudinal myocardial fibers that aremainly distributed in the subendocardium.14,38 This assertionis supported by the autopsy finding of subendocardial ische-mia in severe PE with adverse outcome.9

Gestational HypertensionAlthough women with GH had similar hemodynamic and LVgeometric patterns as women with PE, they did not demon-strate global diastolic or regional systolic abnormalities. Thelatter finding suggests that some cardiac changes in PE arerelated to factors other than hypertension. Although highblood pressure is the sole cardinal feature of GH, hyperten-sion is only 1 of a cluster of signs used to define themultisystem disorder of PE.1 It is possible that coexistence ofoxidative stress and endothelial damage in PE could beresponsible for the diastolic and systolic dysfunction seen inthis condition. Alternatively, the cardiovascular stress pro-voked by PE may have exposed an independent underlyingmyopathic process.

Clinical Implications of the Study FindingsThe findings of this study have significant clinical implica-tions for peripartum intravascular volume management, be-cause the women with global diastolic dysfunction are theones most likely to sustain acute cardiopulmonary morbidity,most commonly from pulmonary edema.8,39–42 The latter maybe better predicted by the early diastolic mitral wave velocity/average lateral and septal diastolic myocardial velocities ratioin patients with global diastolic dysfunction, because it is abetter indirect index of pulmonary capillary wedge pressurethan central venous pressure.42,43 The study findings alsodemonstrate that PE is associated with heart remodeling andsignificant changes in cardiac function. Many of the alteredTD indices are known to be independently related to thelong-term risk of cardiovascular morbidity in nonpregnantsubjects.13,21,31–33,44 A better understanding of the relationshipof these indices and subsequent morbidity in the context ofpregnancy may provide an opportunity for early cardiovas-cular risk stratification and the introduction of prophylacticstrategies.

PerspectiveThe findings of this study indicate that cardiac changes inwomen with PE are mainly adaptive in nature, maintainingcardiac function at the same time as minimizing wall stress

10

5

10

5

15

15

20%

-20%

0

-5

-10

-15

0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.285

HR

SR -6.9% t 1.25 sAVO AVC AVO AVC

Figure 6. Color-encoded tissue Doppler longitudi-nal strain curve recorded at the basal inferoseptalsegment. Segmental shortening (negative strain)throughout systole to an end-systolic maximumdeformation (yellow arrow) followed by a furtherpostsystolic shortening (light blue arrow) duringthe isovolumetric relaxation time. AVO and AVCdenote aortic valve opening and closure,respectively.

V

5

Figure 5. An apical 4-chamber view showing abnormal convex-ity and thickening of the basal septum (arrow) toward the leftventricular cavity in a preeclamptic patient.




and maintaining myocardial oxygen delivery. There wasevidence of myocardial damage in 20% of women with PE inthis study. These women are at highest risk of cardiovascularcomplications in the acute phase of PE and may manifestincreased cardiovascular morbidity and mortality later in life.Clarification of the latter is important from a public healthperspective, because early identification and intervention mayameliorate subsequent cardiovascular disease.

AcknowledgmentsWe are grateful to the midwives and sonographers of the FetalMaternal Medicine Unit, St George’s Hospital, for their invaluablehelp with patient recruitment.

Sources of FundingK.M. was funded for her PhD thesis research by the University ofChieti, Chieti, Italy.

DisclosuresNone.

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Table 5. Summary Hemodynamic, Remodeling, Cardiac Function Indices for Control, Term Gestational Hypertension,and Term PE Pregnancies*

ParameterTerm Control

(n�50)GH

(n�20)PE

(n�50)

GH VersusControl

(P Values)

PE VersusControl

(P Values)PE Versus GH

(P Values)

MAP, mm Hg 83 (74–92) 109 (107–118) 113 (106–120) 0.0001 0.0001 0.4

CI, L/min/m2 3.2 (2.2–3.9) 2.8 (2.4–3.2) 2.9 (2.1–3.8) 0.6 0.6 0.5

TVRI, (dynes�s�1�cm�5)/m2 645 (570–840) 951 (756–1086) 716 (574–1036) 0.003 0.012 0.7

Global diastolic dysfunction 7 (14) 2 (15) 20 (40) 0.9 0.007 0.031

Regional diastolic dysfunction† 3 (7) 0 9 (30) 0.6 0.022 0.028

Total LV geometric abnormality 12 (24) 15 (75) 34 (68) 0.0001 0.0001 0.7

Septal bulge 0 0 7 (14) … 0.019 0.2

LV basal postsystolic shorteningindex �25%

1 (2) 1 (5) 9 (18) 0.9 0.011 0.2

*Values are given as median (interquartile) or no. of patients (percentage).†Regional diastolic dysfunction is computed among patients with normal global diastolic function.MAP indicates mean arterial pressure; CI, cardiac index; TVRI, total vascular resistance index.




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28. Takemoto Y, Pellikka PA, Wang J, Modesto KM, Cauduro S, BelohlavekM, Seward JB, Thomson HL, Khandheria B, Abraham TP. Analysis ofthe interaction between segmental relaxation patterns and global diastolicfunction by strain echocardiography. J Am Soc Echocardiogr. 2005;18:901–906.

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ONLINE SUPPLEMENT

MATERNAL CARDIAC DYSFUNCTION AND REMODELING IN WOMEN

WITH PREECLAMPSIA AT TERM

Short title: Cardiac impairment in preeclampsia at term

Karen Melchiorre1, 2, 3 MD, George Ross Sutherland2 MD, FRCP, Aigul

Baltabaeva2 MD, Marco Liberati3 MD, PhD, Basky Thilaganathan1 MD,

FRCOG

1Fetal Maternal Medicine Unit, Department of Obstetrics and Gynecology,

St George’s Hospital, University of London, London, United Kingdom

2Department of Cardiology and Cardiothoracic Surgery, St George’s Hospital,

University of London, London, United Kingdom

3Department of Obstetrics and Gynecology,

University of Chieti, Chieti, Italy

Correspondence: to Prof. Basky Thilaganathan

Fetal Maternal Medicine Unit

St George’s University of London

Cranmer Terrace

London SW17 0RE

Telephone: 020 8725 0071

Facsimile: 0208725 0079

E-mail: [email protected]



2

Method Calculation of echocardiograhic indices 1. Left ventricle meridian end-systolic stress (ESS) was calculated using cuff

systolic blood pressure (SBP) taken at the end of the echocardiographic examination. ESS meridian = (1.35xSBPxLVESD)/[(4xLVPWs) x (1+{LVPWs/LVESD})], where LVESD is left ventricle end-systolic dimension and LVPWs is left ventricle posterior wall thickness in systole.

2. Stroke volume (SV) was calculated as the product of aortic Doppler flow velocity time integral (VTI) and cross-sectional area of the left ventricle outflow tract (CSA).

3. Cardiac output (CO) was obtained as the product of stroke volume and heart rate (HR) derived from ECG monitoring.

4. Total vascular resistance (TVR) was calculated in dynes x sec-1 x cm-5 according to the formula: TVR = (MAP in mmHg/CO in L/min) × 80.

5. Cardiac work (CW) was calculated using the formula: CW=CO x MAP.



3

Results Tables Table S1. Global diastolic function indices in cases with and without global diastolic dysfunction versus controls. Values are given as either median (interquartile) or number of subjects (percentage). Parameter

Controls

(n=50)

Cases with

normal

diastolic

function (n=30)

Cases with global

diastolic

dysfunction (n=20)

Controls vs cases

with normal

diastolic function

(p values)

Controls vs cases

with diastolic

dysfunction

(p values)

Left atrial remodeling and function

LA area FC (%) 0.74 (0.64-0.88) 0.78 (0.60-0.93) 0.69 (0.59-0.84) 0.6 0.3

LADI (cm/m2) 1.8 (1.7-2.2) 2.1 (1.7-2.5) 2.1 (1.6-2.1) 0.4 0.5

Mitral inflow

E (m/sec) 0.78 (0.62-0.84) 0.79 (0.73-0.95) 0.65 (0.57-0.82) 0.0001 0.9

A (m/sec) 0.64 (0.55-0.76) 0.60 (0.57-0.63) 0.82 (0.76-0.83) 0.2 0.0001

A duration (ms) 95.5 (83-108) 113 (93.8-123) 97 (83-103) 0.2 0.9

Pulmonary venous flow

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S (m/sec) 0.51 (0.44-0.57) 0.45 (0.40-0.61) 0.55 (0.51-0.65) 0.1 0.3

D (m/sec) 0.47 (0.41-0.53) 0.47 (0.40-0.58) 0.43 (0.34-0.52) 0.01 0.6

AR (m/sec) 0.30 (0.26-0.33) 0.26 (0.24-0.27) 0.32 (0.28-0.36) 0.9 0.1

AR duration (ms) 103 (87-116) 107 (94-143) 106 (86-123) 0.01 0.1

Vp (cm/sec) 78 (67-102) 69 (51-135) 64 (52-80) 0.7 0.2

Left atrial and ventricular filling pressure

E/Em basal

inferoseptal wall ratio

10 (8.5-13.4) 12 (9.4-17.6) 13 (9.7-15) 0.006 0.02

E/Em basal

anterolateral wall ratio

7 (6-9) 8.9 (7.3-12) 9.6 (8.8-12.2) 0.08 0.0001

E/Vp ratio 1.2 (0.88-1.5) 1.1 (0.7-1.6) 1.1 (0.9-1.2) 0.2 0.5

LA area FC=left atrial area fractional change; LADI=left atrial dimension index (LAD/BSA); E=peak early diastole transmitral wave velocity; A=peak late diastole transmitral wave velocity; S=peak systolic pulmonary venous flow velocity; D=peak anterograde early diastolic pulmonary venous flow velocity; AR=peak retrograde late diastolic pulmonary venous flow velocity; Vp= Color M-Mode propagation flow velocity; Em= peak early diastolic myocardial velocity;

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Table S2. Regional diastolic function color Doppler myocardial velocities and deformations of cases with and without global diastolic dysfunction and controls. Values are given as median (interquartile) or number of subjects (percentage). Parameter Controls

(n=50)

Cases with normal

diastolic function

(n=30)

Cases with global

diastolic

dysfunction

(n=20)

Controls vs cases

with normal

diastolic function

(p values)

Controls vs cases with

diastolic dysfunction

(p values)

Inferoseptal wall

Basal Em (cm/sec) 7.3 (6-8.2) 7.6 (5.8-8.5) 5.5 (4.8-6.6) 0.9 0.001

Mid Em (cm/sec) 6 (5.3-7.8) 6.5 (5.3-7.8) 5.2 (4-6.4) 0.7 0.008

Basal SRE (1/sec) 2 (1.4-2.4) 1.7 (1.3-2) 1.5 (1-2.3) 0.02 0.1

Mid SRE (1/sec) 1.9 (1.3-2.3) 1.5 (1-2) 1.55 (1.2-1.8) 0.007 0.035

Anterolateral wall

Basal Em (cm/sec) 10 (9-12) 8.9 (7.8-10.9) 7.5 (6.6-8.9) 0.047 0.037

Mid Em (cm/sec) 8.3 (6.6-10) 7.1 (5.3-8.4) 5.3 (4-9) 0.2 0.06

Basal SRE (1/sec) 2 (1.6-2.7) 1.8 (1.2-2.2) 1.8 (1.4-2.8) 0.3 0.5

Mid SRE (1/sec) 2.1 (1.6-3.2) 1.9 (1.4-2.7) 1.5 (1-2.3) 0.4 0.010

Em= peak early diastolic myocardial velocity; SR E= peak early diastolic myocardial strain rate.

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Table S3 Demographic and pregnancy characteristics of cases with and without global diastolic dysfunction. Values are given as median (interquartile range) or number of subjects (percentage). Parameter Cases with normal

diastolic function (n=30)

Cases with global

diastolic dysfunction

(n=20)

P value

Pre-pregnancy characteristics

Maternal age (years) 31 (26-34) 36 (32-39) 0.001

Pre pregnancy BMI (kg/m2) 25.4 (23.4-30.1) 26.8 (24.2-26.8) 0.1

Pre pregnancy BSA (m2) 1.6 (1.4-1.9) 1.7 (1.5-2) 0.2

Nulliparous 22 (73) 12 (60) 0.5

Caucasian 16 (53) 16 (80) 0.1

Pre-clinical characteristics

(before developing PE)

SBP at booking visit (mm Hg) 110 (100-120) 110 (110-120) 0.9

DBP at booking visit (mm Hg) 70 (60-73) 65 (60-78) 0.6

Fasting glucose at booking visit (mmol/L) 4.8 (4.2-5.2) 5.4 (4.6-6.2) 0.1

Clinical characteristics

(at acute PE)

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SBP at assessment (mm Hg) 145 (140-160) 150 (140-165) 0.1

DBP at assessment (mm Hg) 95 (90-100) 100 (90-100) 0.3

Serum creatinine level (mg/dl) 0.6 (0.5-0.7) 0.6 (0.5-0.8) 0.8

Serum albumin level (mg/dl) 0.3 (0.25-0.35) 0.3 (0.27-0.35) 0.09

24-h protein urine collection (g/24h) 1 (0.9-1.4) 1 (0.9-1.5) 0.9

ALT (IU/L) 17 (12-29) 15 (13-32) 0.9

PLT count (x109/L) 250 (200-295) 215 (170-260) 0.2

Htc (%) 34 (31-36) 36 (34-37) 0.4

Hb (g/dl) 11.4 (10.4-12.3) 11 (12-12.7) 0.1

Pregnancy outcome

Maternal acute complications

(3 HELLP syndrome, 1 renal failure, 1

pulmonary edema)

1 (3) 4 (20) 0.2

Fetal growth restriction 5 (17) 6 (30) 0.4

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BMI=body mass index; BSA=body surface area; SBP=systolic blood pressure; DBP=diastolic blood pressure; ALT=alanine transaminase; PLT=platelet count; Htc=hematocrit; Hg=hemoglobin; HELLP=hemolysis, elevated liver enzymes, low platelet count.

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Table S4. LV remodeling parameters of cases with and without global diastolic dysfunction and controls. Values are given as median (interquartile) or number of subjects (percentage). Parameter Controls

(n=50)

PE with normal

global diastolic

function (n=30)

PE with global

diastolic

dysfunction

(n=20)

Controls vs cases

with normal

diastolic function

(p values)

Controls vs cases

with diastolic

dysfunction

(p values)

IVSd (cm) 0.8 (0.7-0.9) 1 (0.9-1.1) 0.9 (0.8-1) 0.0001 0.0001

IVSs (cm) 1 (1-1.1) 1.3 (1.1-1.4) 1.1 (1.1-1.3) 0.0001 0.003

LVPWd (cm) 0.8 (0.7-0.9) 1 (0.9-1.1) 1 (0.9-1.1) 0.0001 0.0001

LVPWs (cm) 1.2 (1-1.3) 1.4 (1.3-1.6) 1.3 (1.2-1.4) 0.0001 0.02

LVEDDI (cm/m2) 2.5 (2.2-2.8) 2.4 (1.9-2.8) 2.1 (1.7-2.7) 0.09 0.019

LVESDI (cm/m2) 1.8 (1.5-2) 1.6 (1.1-1.9) 1.6 (1.2-2) 0.1 0.041

LVMI 1 (g/h2.7) 27.6 (24.1-36.2) 38 (31-45) 37 (34-44) 0.0001 0.0001

LV=left ventricle; IVSd=interventricular septum wall thickness at diastole; IVSs=interventricular septum wall thickness at systole; LVPWd=left ventricular posterior wall thickness at diastole; LVPWs=left ventricular posterior wall thickness at systole; LVEDDI=left ventricular end diastolic dimension index; LVESDI=left ventricular end systolic dimension index; LVMI 1=left ventricular mass index 1 (LVM normalized for height raised at 2.7).

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Table S5. LV global longitudinal systolic function indices of cases with and without global diastolic dysfunction and controls. Values are given as median (interquartile). Parameter

Controls (n=50)

PE with normal global

diastolic function (n=30)

PE with global diastolic

dysfunction (n=20)

Controls vs cases with normal

diastolic function (p values)

Controls vs cases with diastolic dysfunction (p values)

Mitral valve annulus septal siteMitral ring

displacement (mm) 11.7 (10.2-13.3) 14.2 (12.8-19.2) 10.7 (9-12) 0.4 0.6

S1 (cm/sec)

9 (7.3-9.8) 7 (6.3-7) 7 (6-8) 0.014 0.03

Long axis shortening (%)

1.4 (1.2-1.8) 1.9 (1.6-2.8) 1.4 (1.2-1.6) 0.09 0.8

S1/LAX (1/sec)

1.1 (0.9-1.2) 0.9 (0.88-0.93) 0.97 (0.85-1.1) 0.1 0.06

Mitral valve annulus lateral site

Mitral ring displacement (mm)

12.6 (11.1-14.5) 11.5 (9.9-13.6) 12.2 (9.7-15) 0.02 0.8

S1

(cm/sec) 8.5 (7-9.8) 7.5 (5.3-9) 7 (7-9) 0.5 0.2

Long axis shortening (%)

1.7 (1.3-1.9) 1.6 (1.3-1.8) 1.7 (1.3-1.9) 0.1 0.6

S1/LAX (1/sec)

1.1 (0.9-1.3) 1 (0.8-1.2) 1 (0.9-1.1) 0.2 0.1

Strain rate study (8 segments model)

Peak systolic strain rate index

(1/sec)

1.57 (1.34-1.66) 1.50 (1.34-1.58) 1.3 (1.10-1.75) 0.2 0.4

Peak systolic strain rate index/LV LAX

0.20 (0.17-0.23) 0.19 (0.17-0.23) 0.18 (0.14-0.24) 0.3 0.6

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(1/sec/cm) S1=pulsed wave Doppler peak systolic velocity; LV= left ventricle; LAX: end-diastolic LV long axis length; long axis shortening=mitral ring displacement normalized for LAX (expressed in mm). S1/LAX =pulsed wave Doppler peak systolic velocity normalized for LAX (expressed in cm).

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Table S6. LV radial systolic function conventional and tissue Doppler indices of cases with and without global diastolic dysfunction and control group. Values are given as median (interquartile) or number of subjects (percentage). Parameter Controls (n=50) PE with normal

global diastolic function

(n=30)

PE with global diastolic

dysfunction (n=20)


normal diastolic function

(p values)

Controls vs cases with diastolic

dysfunction

(p values) Conventional indices

EF (%)

60 (55-64) 57 (52-64) 62 (51-69) 0.1 0.8

FS (%)

28 (26-33) 29 (25-36) 28 (24-32) 0.5 0.7

ESV I (ml/m2)

20.6 (13.6-26.2) 16 (14-21) 21.7 (19.2-26.1) 0.5 0.014

EDV I (ml/m2)

45 (37-60) 55 (44-61) 44 (37-59) 0.051 0.9

Myocardial velocity and deformation indices

Mid Sm (cm/sec)

4.5 (3.9-5.2) 3.7 (3.2-5.2) 5 (4.3-5.7) 0.05 0.1

Mid Peak systolic strain rate (1/sec)

2 (1.7-2.8) 2.3 (1.8-2.6) 2.3 (1.8-2.7) 0.6 0.6

Mid End systolic strain (%)

44 (37-60) 49 (43-55) 45 (38-59) 0.2 0.7

Mid Sm/LV SAX (1/sec)

0.98 (0.76-1.19) 0.78 (0.66-1.2) 1.1 (0.93-1.2) 0.09 0.1

Mid peak systolic strain rate/LV SAX

(1/sec/cm)

0.49 (0.36-0.59) 0.48 (0.40-0.62) 0.51 (0.40-0.63) 0.6 0.3

Mid end systolic strain/LV SAX (%/cm)

10.5 (7.8-12.6) 10.7 (9.6-13.3) 11.3 (8.6-12.3) 0.3 0.4

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EF=ejection fraction; FS=fractional shortening; BSA=body surface area; EDVI=left ventricular end diastolic volume index (EDV/BSA); ESVI=left ventricular end systolic volume index (ESV/BSA). Myocardial velocities and deformation indices: Sm =peak systolic myocardial fibers velocity; LV=left ventricle; SAX=end-diastolic short axis length in cm.

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Table S7. LV regional longitudinal systolic function color tissue Doppler indices of cases with and without global diastolic dysfunction versus control group. Values are given as median (interquartile) or number of patients (percentage). Parameter Controls (n=50) Cases with

normal diastolic

function (n=30)

Cases with global diastolic

dysfunction (n=20)


normal diastolic function (p

values)

Controls vs cases with diastolic

dysfunction (p values)

Inferoseptal wall Basal Sm (cm/sec)

5.7 (4.8-6.4) 5.3 (4.5-6.8) 5.6 (5.1-6.3) 0.6 0.5

Basal peak systolic strain rate (1/sec)

1.4 (1.2-2) 1.2 (0.9-1.6) 1.1 (1-1.3) 0.014 0.018

Basal end systolic strain (%)

20 (17-25) 16 (13-19.7) 17.5 (14.3-22) 0.008 0.016

Basal post-systolic strain Number (%)

13 (26) 7 (23) 10 (50) 0.6 0.1

Basal post-systolic strain index > 25% Number (%)

0 3 (10) 5 (25) 0.09 0.002

Mid Sm (cm/sec)

4.7 (3.6-5.4) 4.3 (3.4-5.4) 4.7 (3.8-5.5) 0.7 0.7

Mid Peak systolic strain rate (1/sec)

1.5 (1.2-1.8) 1.3 (1.1-1.6) 1.2 (1-1.6) 0.6 0.2

Mid end systolic strain (%)

23 (18-27) 19 (15-23) 18 (16-24) 0.06 0.05

Basal Sm/LV LAX (1/sec)

0.7 (0.6-0.9) 0.7 (0.6-0.9) 0.7 (0.7-0.8) 0.2 0.3

Basal peak systolic strain rate/ LV LAX (1/sec/cm)

0.20 (0.15-0.28) 0.15 (0.11-0.21) 0.14 (0.13-0.16) 0.05 0.03

Basal end systolic strain/ LV LAX (%/cm)

2.7 (2.3-3.2) 2.2 (1.7-2.7) 2.3 (1.9-3.1) 0.05 0.02

Mid Sm/ LV LAX (1/sec)

0.6 (0.5-0.7) 0.5 (0.4-0.8) 0.6 (0.5-0.7) 0.7 0.8

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Mid peak systolic strain rate/ LV LAX (1/sec/cm)

0.18 (0.15-0.25) 0.17 (0.15-0.25) 0.22 (0.18-0.30) 0.9 0.2

Mid end systolic strain/ LV LAX (%/cm)

2.9 (2.1-3.4) 2.6 (2-3.3) 2.5 (2-2.9) 0.3 0.1

Anterolateral wall

Basal Sm (cm/sec)

6 (4.9-7.4) 4.6 (4-5.7) 5.3 (5-6.1) 0.02 0.4

Basal peak systolic strain rate (1/sec)

1.4 (1-2) 1.38 (1-1.7) 1.7 (1.4-2.3) 0.6 0.3

Basal end systolic strain (%)

20 (17-27) 19 (16-26) 23 (17-27) 0.5 0.2

Basal post-systolic strain Number (%)

6 (12) 6 (20) 4 (20) 0.5 0.6

Basal post-systolic strain index > 25% Number (%)

1 (2) 1 (3) 1 (5) 0.7 0.9

Mid Sm (cm/sec)

5 (4-6.6) 3.7 (2.6-4.5) 4.2 (3.1-5.1) 0.008 0.4

Mid peak systolic strain rate (1/sec)

1.4 (1-1.8) 1.4 (0.9-1.7) 1.1 (1-1.7) 0.4 0.2

Mid end systolic strain (%)

20 (16-24) 18 (15-22) 17 (12-21) 0.2 0.018

Basal Sm/ LV LAX (1/sec)

0.8 (0.6-1) 0.6 (0.5-0.8) 0.7 (0.6-0.8) 0.1 0.7

Basal peak systolic strain rate/ LV LAX (1/sec/cm)

0.18 (0.15-0.28) 0.17 (0.14-0.25) 0.23 (0.19-0.31) 0.9 0.2

Basal end systolic strain/ LV LAX (%/cm)

2.5 (2.1-2.4) 2.7 (2-3.3) 3 (2.3-3.7) 0.9 0.1

Mid Sm mid/ LV LAX (1/sec)

0.69 (0.49-0.91) 0.48 (0.37-0.64) 0.55 (0.43-0.69) 0.03 0.6

Mid peak systolic strain rate/ LV LAX (1/sec/cm)

0.18 (0.14-0.23) 0.17 (0.13-0.21) 0.14 (0.13-0.23) 0.5 0.3

Mid end systolic strain/ LV LAX (%/cm)

2.5 (2.1-3.2) 2.4 (2.2-2.9) 2.2 (1.7-2.7) 0.4 0.05

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Sm =peak systolic myocardial fibers velocity; LV= left ventricle; LAX=end-diastolic long axis length (expressed in cm).

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Table S8. Multiple regression analysis (stepwise method) between diastolic function indices (dependent variables) and cardiac parameters of systolic function, hemodynamic and remodeling, demographic and pregnancy characteristics (independent variables) Model

summary DBP SBP MAP LVMI Age Septal long

axis shortening

Lateral long axis shortening

R p β (p) β (p) β (p) β (p) β (p) β (p) β (p) Transmitral inflow indices E/A 0.63 0.0001 -0.46

(0.002) NS NS NS -0.35

(0.015) NS NS

DT 0.72 0.0001 0.46 (0.001)

NS NS NS NS NS NS

IVRT 0.45 0.004 0.45 (0.004)

NS NS NS NS NS NS

TD myocardial relaxation indices Lateral E1 0.52 0.015 NS NS NS -0.52

(0.015) NS NS NS

Septal E1 0.44 0.039 NS NS NS NS NS 0.44 (0.039)

NS

Lateral E1/A1 0.64 0.008 NS -0.45 (0.029)

NS NS NS NS 0.62 (0.004)

Septal E1/A1 0.83 0.0001 NS -0.49 (0.002)

NS -0.30 (0.036)

NS 0.74 (0.0001)

NS

Filling pressure indices Lateral E/E1 0.74 0.001 NS NS 0.46

(0.025) NS NS NS -0.89

(0.0001) Septal E/E1 0.64 0.001 NS NS NS 0.64

(0.001) NS NS NS

Average E/E1 0.66 0.001 NS NS NS 0.66 (0.001)

NS NS NS

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R=multiple correlation coefficient; β=Standardized beta coefficient. E/A=early diastole peak transmitral wave velocity to late diastole peak transmitral wave velocity ratio; DT=deceleration time of E wave; IVRT=isovolumetric relaxation time; E1=pulsed Doppler peak early diastolic velocity at mitral valve annulus; A1=peak late diastolic velocity at mitral valve annulus; SBP=systolic blood pressure; DBP=diastolic blood pressure; MAP=mean arterial pressure; LVMI=left ventricle mass index; long axis shortening=mitral ring displacement normalized for left ventricle end-diastolic long axis length. NS=not significant. Only indices found to be significantly independently correlated to diastolic function indices are shown in the table.

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Table S9. Intra and inter-observer coefficients of variation, 95% limits of agreement, repeatability coefficients, within-subjects standard deviations (SD) for conventional echocardiographic and tissue Doppler velocity and deformation indices Intra-observer indices Inter-observer indices

Parameter Coefficient

of

variation

95%Limits of

agreement

Repeatability

Coefficient

Within-

subjects

SD

Coefficient

of

variation

95%Limits of

agreement

Repeatability

Coefficient

Within-

subjects SD

2D, M-mode and color Doppler indicesM-mode LVM 2.64 -9.67 to 6.03 8.26 2.98 7.59 -24.41 to 25.76 23.83 8.64

M-mode RWT 5.76 -0.044 to 0.084 0.072 0.026 7.95 -0.116 to 0.068 0.099 0.036

EF 4.88 -8.35 to 8.75 8.12 2.93 6.27 -10.21 to 11.48 10.36 3.73

CO 4.14 -0.52 to 0.58 0.52 0.19 5.21 -0.73 to 0.62 0.65 0.23

TVR 3.34 -196.7 to 183.9 181.0 65.3 5.85 -215 to 192 195.0 72.3

E 2.59 -0.057 to 0.053 0.052 0.018 3.82 -0.087 to 0.043 0.075 0.027

A 4.26 -0.051 to 0.087 0.074 0.027 6.96 -0.174 to 0.080 0.151 0.054

DT 1.67 -11.41 to 9.41 10.07 3.63 0.57 -33.26 to 20.06 28.41 10.25

IVRT 3.12 -9.59 to 7.39 8.33 3.01 3.78 -5.61 to 11.61 10.07 3.63

Adur 3.12 -10.55 to 7.75 9.10 3.28 4.02 -13.15 to 11.55 11.82 4.26

S 1.91 -0.034 to 0.019 0.028 0.010 5.61 -0.09 to 0.058 0.076 0.027

D 2.33 -0.022 to 0.014 0.019 0.01 4.56 -0.06 to 0.03 0.05 0.018

AR 8.04 -0.060 to 0.080 0.069 0.025 5.66 -0.033 to 0.055 0.047 0.017

ARdur 3.87 -13.867 to 10.66 12.05 4.34 3.73 -13.75 to 10.55 11.95 4.31

Color M-mode Vp 11.62 -22.34 to 12.74 19.12 6.89 8.48 -16.58 to 13.78 14.66 5.29

M-Mode LAD 3.12 -0.19 to 0.35 0.30 0.109 6 -0.66 to 0.22 0.60 0.21

2-D LAV 2.16 -3.83 to 2.23 3.27 1.18 8.06 -5.96 to 13.56 11.8 4.28

Longitudinal Color Tissue Doppler velocity and deformation indices

Sm 7.3 -0.98 to 0.86 0.91 0.32 11.34 -1.32 to 1.61 1.45 0.52

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End-systolic strain 6.69 -2.58 to 4.10 3.58 1.29 7.9 -14.40 to 10.17 12.67 4.57

Em 8.89 -0.98 to 1.92 1.69 0.61 9.76 -1.21 to 2.92 1.87 0.81

Am 11.55 -1.23 to 1.42 1.31 0.47 11.78 -2.29 to 1.94 2.09 0.75

Peak systolic SR 6.21 -0.15 to 0.24 0.21 0.07 8.08 -0.36 to 0.19 0.32 0.11

Peak ESR 11.96 -0.67 to 0.59 0.62 0.22 7.4 -0.37 to 0.31 0.34 0.12

Peak ASR 7.59 -0.32 to 0.24 0.28 0.10 7.5 -0.23 to 0.30 0.27 0.10

Displacement 4.11 -1.34 to 1.41 1.34 0.48 8.11 -3.27 to 2.46 2.90 1.04

Radial Color Tissue Doppler velocity and deformation indices

Sm 10.03 -1.41 to 1.24 1.27 0.45 11.76 -1.49 to 1.65 1.49 0.54

End-systolic strain 5.59 -5.81 to 7.11 6.26 2.26 10.53 -14.19 to 7.37 12.21 4.41

Peak systolic SR 8.13 -0.60 to 0.43 0.52 0.18 7.08 -0.43 to 0.36 0.39 0.14

Longitudinal Pulsed Tissue Doppler velocity indices

E1 2.91 -0.87 to 0.76 0.80 0.28 6.71 -2.15 to 1.60 1.90 0.68

A1 3.84 -1.02 to 1.11 1.03 0.37 5.56 -1.75 to 1.19 1.53 0.55

LVM=left ventricular mass; RWT=relative wall thickness; EF=ejection fraction; CO=cardiac output; TVR=total vascular resistance; E=peak early diastole transmitral wave velocity; A=peak late diastole transmitral wave velocity; DT=deceleration time of E wave; IVRT=isovolumetric relaxation time; Adur= mitral A wave duration. Pulmonary venous waveforms indices: S=peak systolic velocity; D=peak anterograde early diastolic velocity; AR=peak retrograde late diastolic velocity; ARdur=AR duration. Vp= Colour M-Mode propagation flow velocity; LAD=left atrial dimension; LAV= left atrial volume; Sm= color tissue Doppler peak systolic myocardial velocity; Em= color tissue Doppler peak early diastolic myocardial velocity; Am= color tissue Doppler peak late diastolic myocardial velocity; SR=strain rate; ESR=early diastolic strain rate; ASR: late diastolic strain rate; E1= pulsed wave tissue Doppler peak early diastolic velocity at mitral valve annulus; A1= pulsed wave tissue Doppler peak late diastolic velocity at the mitral valve annulus.

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Maternal Cardiac Dysfunction and Remodeling in Women With Preeclampsia at Term

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