Discussion
In this exploratory study we demonstrate an echocardiographic evidence
that suggests a subclinical increase in estimated mean PAP and estimated
PVR, and a modest decrement in RV function in patients with an
established diagnosis of early and late PEC compared with age- and
gestationally- matched pregnant controls. Pulmonary artery acceleration
time at cut off value of 100 ms differentiated patients with early PEC
compared with controls, substantiating the likelihood of increased PA
pressure. Likewise, validated equations that estimate mean PAP based on
PAAT revealed an increase in estimated MPAP in PEC compared with
controls. Estimated PVR was significantly elevated in both early and
late PEC compared to controls. We detected significantly increased RV
MPI and reduced mid-point TTAD in early PEC, but the change in RVMPI did
not reach the threshold that is considered to be clinically significant
(RVMPI>5), and other parameters of RV function, such as RV
FAC, indexed RV SV, indexed RV CO, TAPSE, and TV S’ were unchanged. In
the absence of clinical or echocardiographic evidence of valvular, or
systolic, or diastolic LV dysfunction, we speculate that the increased
estimated MPAP, decreased PAAT and increased estimated PVR are due to a
pulmonary vascular phenomenon rather than a left heart disease etiology.
Our study highlights the value of echocardiography as a safe and
non-invasive tool in the assessment of cardiac structure and function in
PEC patients.
Non-invasive assessment of the pulmonary circulation and RV function and
structure in PEC is an evolving area of investigation. We are aware of
only two studies assessing PA flow dynamics non-invasively in PEC, and
both studies corroborate our findings in general, although by using
slightly different methodology, without distinguishing between early and
late onset PEC and without excluding patients with severe PEC[17,
18]. Importantly, although the gold standard for diagnosing PAH is
right heart catherization, it is invasive and increases the risk of
maternal and fetal radiation exposure. Echocardiographic estimation of
PAP provides an invaluable non-invasive and safe screening tool for
increased PA pressure that warrants further follow up and investigation.
Similarly, echocardiography is a more feasible, bedside option of
measuring RV function and structure compared to the gold standard,
cardiac magnetic resonance imaging[19].
A recent meta-analysis of 21 published studies indicate that estimation
of mean PAP using PAAT shows very good correlation with values obtained
using catheterization, that a cutoff value of PAAT<100 ms has
84% sensitivity and 90% specificity in the diagnosis of pulmonary
hypertension and that PAAT can be reliably measured in
>90% of patients[14]. In our study we used both the
method of using the PAAT<100ms cutoff value and also the
estimation of MPAP to test whether there is evidence for increased PAP
in PEC.
In our early PEC cohort, we found estimated mean PAP to be above the
maximum of normal range. Both Caglar et al.[17] and Vaught et
al.[18] found significantly increased estimated PA pressures in
preeclamptic patients, but their reported values were below or at the
limit of maximum normal pressure (20mmHg). The difference could be
methodological, since they used TV regurgitant jet velocity for their
estimate and we based our estimate on PAAT. Alternatively, the
difference may be in the patient cohort analyzed as our findings suggest
a greater effect in early PEC, and Caglar et al[17]. and Vaught et
al. [18] did not analyze early PEC separately.
Our study is the first to assess TTAD in preeclamptic patients. TTAD
detects the systolic displacement of the TV annulus, relative to the
apex, at three points. As such, TTAD serves as a surrogate of the
longitudinal deformation of the tricuspid valve annulus. The lateral
point of TTAD (TTAD L) shows close correlation with TAPSE and mid-point
TTAD (TTAD MP) has been shown to be more predictive of RV dysfunction in
patients with PAH compared with TAPSE[20] and to better correlate
with cardiac magnetic resonance imaging-measured RV EF[21]. As such,
TTAD L did not show a difference between controls and PEC, whereas TTAD
MP was significantly decreased in early PEC vs early controls.
Reduced RV function in PEC was shown by previous studies, yet with the
use of different indices of assessment[17, 22]. The study by
Melchiorre et al. [22] demonstrated biventricular increased wall
thickness, and diastolic dysfunction, as well as reduced LV EF and
cardiac output. Comparatively, we did not find a change in cardiac
output or a biventricular diastolic dysfunction. These differences may
be related to the study population. Our study did not include women with
the diagnosis of severe PEC, and we excluded patients with low EF,
whereas the study by Melchiorre et al [22] did not use these
exclusions. Additionally, the latter study used TDI to assess strain and
strain rate, a technique that suffers from some limitations[23]. The
study by Vaught et al .[18] was consistent with our finding of
increased RV MPI in PEC patients compared with controls, yet it
demonstrated biventricular hypertrophy. This difference may be related
to the study population. Vaught et al[18] studied parturients with
early PEC and severe findings and we excluded patients with the
diagnosis of severe preeclampsia. Collectively, our study aligns with
the literature in terms of the presence of subclinical decrement in RV
function and increased PA pressure in patients with early PEC. Notably,
the mild changes in RV function can be considered to be subclinical.
Whether the mildly reduced RV function is a consequence of increased
afterload or whether it develops independently due to circulating
mediators is yet to be determined. Intriguingly, a recent study found
persistent abnormalities in RV function in women who formerly had early
onset PEC for up to three years post-delivery[24].
Preexisting pulmonary arterial hypertension (PAH) portends an increased
mortality in pregnancy and current recommendation for patients with
preexisting pulmonary hypertension is to avoid becoming pregnant, due to
a 15-40% incidence of mortality among women who become pregnant with
preexisting PAH[25]. There is evidence that PEC and PAH share common
mechanisms in their etiology [7, 26-29]. Therefore, we reason that
changes in the pulmonary circulation and right ventricle function in PEC
warrant further investigation.
Our study is limited by its small sample size and needs to be validated
using a larger cohort that will also allow correlating echocardiographic
estimates of MPAP and PVR with indices of disease severity. The small
sample size precludes appropriate adjustment for comorbidities, which
should be addressed in subsequent larger studies. Seven of the nineteen
PEC patients in this study received anti-hypertensive therapy during the
echo exam, which may have altered the echocardiographic findings
compared with controls. However, none of the three drugs, labetalol,
hydralazine or nifedipine are likely to cause an increase in PA pressure
as we observed in this study in the PEC group. Instead, all three drugs
have been proposed in the past to be used to treat PAH, although they
were not shown to be effective. Given the cross-sectional design of our
study, our echo exams were conducted very close to delivery. Hence the
findings may represent a mixed pattern of pregnancy and labor rather
than a single pattern. This can be remedied by studying serial exams in
future studies. While PEC and control patients were matched by
gestational age, there may be likely other systematic differences
between the groups that could confound the results. Furthermore, due to
the lack of 3-D capability of our echocardiography instrumentation at
the time of the study, we were unable to measure 3-D volumetric LV EF,
known to be more accurate echocardiographic modality of measurement of
LV EF[30]. Furthermore, due to the lack of suitable apical LV 2
chamber views, we were unable to measure 2-D LVEF using the biplane
modified Simpson methodology. The area-length method of LVEF estimation
suffers from the limitations of geometric assumption of LV shape as well
as sensitivity to foreshortening and wall distortions[9]. Yet, none
of our patients had diseases that would lead to LV wall motion
abnormalities known to affect the accuracy of this methodology. Rather,
we used the area-length methodology to estimate LV EF as recommended by
the American Society for Echocardiography and European Society of
Cardiovascular Imaging. A normal LV FAC and the absence of clinical
history or symptomatology of heart failure make us deduct that the
elevated estimated MPAP is not due to a left heart pathology.
It is to be emphasized that echocardiographic indices of PAH are only
estimations and they are used to raise the probability of PAH rather
than to establish a conclusive PAH diagnosis.
In conclusion, non-invasive assessment of PA hemodynamics and RV
function may have utility in assessing the cardiovascular status of PEC
patients. Our findings suggest that there is an increase in estimated
MPAP and estimated PVR in PEC, particularly in case of early onset.
There is some evidence of a parallel mild deterioration of RV function,
the significance of which is yet to be determined in future longitudinal
studies. An adequately powered longitudinal study would also assess
whether there is a correlation between echocardiographic findings of
pulmonary hemodynamics and maternal and fetal outcomes and to assess
responsiveness to antihypertensive therapy.
Acknowledgements/Sources of
funding
Supported by the CounterACT Program, National Institutes of Health
Office of the Director (NIH OD), the National Institute of Neurological
Disorders and Stroke (NINDS), and the National Institute of
Environmental Health Sciences (NIEHS), Grant Numbers= (UO1 ES027697) to