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Myocardial dysfunction in fetuses exposed to intraamniotic infection: new insights from tissue Doppler and strain imaging
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Myocardial dysfunction in fetuses exposed to intraamniotic infection: new insights from tissue Doppler and strain imaging Edoardo Di Naro, MD; Antonella Cromi, PhD; Fabio Ghezzi, MD; Alessandra Giocolano, MD; Annamaria Caringella, MD; Giuseppe Loverro, MD OBJECTIVE: The purpose of this study was to assess myocardial func-
RESULTS: Fetuses with intraamniotic infection exhibit impairment in both
tion of fetuses who were exposed to intraamniotic infection compared with fetuses of uncomplicated pregnancies by the application of tissue Doppler and strain rate (SR) imaging.
diastolic and systolic performance, which was characterized by increased diastolic compliance (increased Em/Am ratio, increased early diastolic SR compared with the control fetuses), decreased systolic contractile function (reduced systolic strain and SR), and longitudinal myocardial dyskinesia.
STUDY DESIGN: We evaluated the right ventricular function of fetuses
with preterm premature rupture of membranes and proven intraamniotic infection (n ⫽ 12 fetuses) and healthy fetuses (n ⫽ 27). Tissue Doppler velocities during early diastolic relaxation (Em) and atrial contraction (Am) and early diastolic SR were measured as indices of diastolic function, whereas the peak systolic strain and SR were used as parameters of systolic function.
CONCLUSION: New echocardiographic tools suggest that fetal heart is
a target organ in the context of intraamniotic infection. Key words: fetal heart, fetal inflammatory response syndrome, intraamniotic infection, myocardium, preterm, strain, tissue Doppler imaging
Cite this article as: Di Naro E, Cromi A, Ghezzi F, et al. Myocardial dysfunction in fetuses exposed to intraamniotic infection: new insights from tissue Doppler and strain imaging. Am J Obstet Gynecol 2010;203:459.e1-7.
T
he term fetal inflammatory response syndrome (FIRS) was coined for the first time in 1997 to indicate the fetal counterpart of the systemic inflammatory response syndrome (SIRS) that originally was described in adults.1 SIRS results from the systemic response of the body to infection and is characterized by activation and amplification of various proinflammatory and antiinflammatory
From the Department of Obstetrics and Gynecology, University of Insubria, Varese (Drs Cromi and Ghezzi), and the Third Department of Obstetrics and Gynecology, University of Bari, Bari (Drs Di Naro, Giocolano, Caringella, and Loverro), Italy. Received March 1, 2010; revised May 2, 2010; accepted June 15, 2010. Reprints: Edoardo Di Naro, MD, Department of Obstetrics and Gynecology, University of Bari, Ospedale Consorziale Policlinico, Piazza Giulio Cesare, 70100 Bari, Italy. [email protected]. Authorship and contribution to the article is limited to the 6 authors indicated. There was no outside funding or technical assistance with the production of this article. 0002-9378/$36.00 © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.06.033
pathways. The effects of these overwhelming pro- and antiinflammatory stimuli culminate with the progressive and sequential dysfunction of several organ systems that range from a mild degree of physiologic derangement in individual organs to frank multiple organ failure and ultimately death. Myocardial depression is a well-recognized manifestation of organ dysfunction in SIRS and accounts for much of the associated morbidity and mortality rates. FIRS occurs in a fraction of fetuses who are exposed to intraamniotic infection and is associated with impending preterm delivery, higher risk of perinatal death, serious neonatal morbidity, and long-term sequelae.2,3 Despite differences in fetal and adult immune systems, FIRS demonstrates a substantial degree of similarity with SIRS/sepsis both in underlying molecular mechanisms and in clinical patterns, which include progression toward multisystem organ involvement. Similar to adult syndrome, fetal heart has been suggested to be a target organ during FIRS, and cardiac diastolic dysfunction has been detected by conventional Doppler examination of intracardiac blood flow velocities in fetuses with preterm premature rupture of
membranes (PPROM), particularly in those fetuses with a proven intraamniotic infection.4 Over the last 10 years, technologic advances in signal processing made it possible to measure directly myocardial wall motion velocity, the magnitude of tissue deformation (myocardial strain), and the rate at which deformation occurs (strain rate [SR]), which has provided information on myocardial properties and mechanics that would otherwise be unavailable. In the adult, assessment of diastolic and systolic function by analysis of tissue Doppler velocity data, strain, and SR has been validated extensively. Application of tissue Doppler imaging (TDI) and SR imaging (SRI) to the fetus with and without heart disease has been reported only in recent times,5-11 and such tools have emerged by promising to quantify fetal cardiac function objectively and accurately, which is an objective that has long been considered almost elusive. TDI- and SRI-derived parameters have not been used so far for the assessment of fetal cardiac performance in the context of intrauterine infection/inflammation. Thus, we designed this study to assess myocardial function of fetuses of women
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with PPROM and proven microbial invasion of the amniotic cavity (MIAC), compared with fetuses of women with uncomplicated pregnancies, by applying echocardiographic measurement of tissue velocity, strain, and SR.
M ATERIALS AND M ETHODS Patient population The study population consisted of fetuses whose mothers were admitted between April 2007 and September 2009 with the diagnosis of PPROM between 24 and 34 weeks of gestation and who were offered amniocentesis for the evaluation of the microbial status of the amniotic cavity. Inclusion criteria were (1) singleton gestation, (2) certain gestational age, (3) absence of chromosomal abnormality or congenital malformations detected pre- or postnatally, (4) estimated fetal weight on ultrasound ⬎10th percentile, and (5) microbiologically proven intraamniotic infection (positive amniotic fluid culture). The diagnosis of PPROM was supported by the detection of a pool of fluid in the posterior vaginal fornix on sterile speculum examination and was confirmed by Nitrazine testing for an alkaline pH. Tocolytic agents, antibiotics, and steroids were not administered before maternal blood and amniotic fluid were collected. Calculation of gestational age was based on reliable recollection of the last menstrual period and confirmed or modified by ultrasound scans within the first 14 weeks of gestation. The comparison group consisted of fetuses whose mothers had an uncomplicated pregnancy and were referred for fetal echocardiography. Indications for referral were related to family history of congenital heart anomaly or suspected arrhythmia that had been ruled out. We excluded fetuses of mothers with systemic diseases, such as maternal diabetes mellitus or systemic lupus erythematosus, and fetuses with chromosomal or any other congenital anomaly. Anthropometric parameters were measured in all fetuses to rule out the possibility of growth restriction. We decided to enroll at least 2 healthy control fetuses per case; we prolonged enrollment until the de459.e2
www.AJOG.org sired number of study subjects was achieved. The study was approved by the Institutional Review Board Committee of University of Bari. Written informed consent was obtained from all the participants.
Sonographic evaluation The ultrasound examinations were performed with an Aloka ProSound Alpha 10 (Aloka, Tokyo, Japan), which was equipped with a phased-array duplex multifrequency transducer. All participating patients underwent a full morphologic examination of the fetal heart before quantitative assessment of right ventricular function with TDI and SRI techniques. A single investigator (E.D.N.) performed all fetal echocardiography studies. For each fetus, a highresolution, zoomed loop of the apical 4-chamber view that incorporated at least 3 complete cardiac cycles was recorded. A narrow sector angle was used, and image depth was adjusted to allow for a maximal acquisition frame rate. Special care was taken to align the interventricular septum with the ultrasound beam (angulation, ⬍30 degrees), and no angle correction was carried out. Digital loops were transferred to a dedicated workstation for offline analysis. Longitudinal segmental contraction and relaxation velocities of the right ventricle myocardium and strain and SR measurements were obtained by the technique described by Perles et al.9 Briefly, myocardial velocity profile was recorded by placement of the region of interest in the basal portion of the right free ventricular wall, adjacent to the tricuspid annulus. For strain and SR analysis, the region of interest was selected in the mid onethird of the right ventricle free wall. Through spatial derivation of the velocity data along the myocardial section of interest, Doppler-derived SR can be obtained. Further temporal integration of the SR will extract Doppler-derived strain. Two-dimensional echocardiography was used to record aortic valve closure and atrioventicular valves opening and closure, which were used for timing events during the cardiac cycle. By convention, strain is defined as positive when the distance between the points of
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measurements is increasing (ie, lengthening); shortening is represented by negative strain. Correspondingly, normal ventricular myocardium has a negative SR in systole and a positive SR during diastole. The following parameters were measured and averaged over 3 cycles: tissue Doppler velocities during early diastolic relaxation (Em) and atrial contraction (Am) and early diastolic SRs, as indices of right ventricle diastolic function and the peak systolic strain and SR as parameters of systolic function. Em/Am ratio was calculated as a surrogate measure of overall diastolic function.
Specimen collection and histologic examination In the study group, amniocentesis was performed with a 21-gauge needle under ultrasonographic guidance with a freehand technique. A sample of amniotic fluid was sent to the laboratory in a capped syringe immediately after collection for white blood cell count determination and cultures. Amniotic fluid was cultured for aerobic and anaerobic bacteria and for Mycoplasmas. At delivery, tissue samples were obtained from the umbilical cord and placenta. Histologic chorioamnionitis was defined as the presence of acute inflammatory changes in any of the placental tissue samples (amnion, chorion-decidua, and chorionic plate). Funisitis was diagnosed in the presence of neutrophilic infiltration in the umbilical cord wall vessels or in the Wharton’s jelly. Statistical analysis Statistical analysis was performed with GraphPad Prism (version 5.0c for Macintosh; GraphPad Software, San Diego CA). The t test and the Mann Whitney U test were used to compare continuous parametric and nonparametric variables, respectively. Proportions were analyzed with Fisher’s exact test. Because myocardial tissue velocity increases as a function of gestational age, the difference between the observed value and the mean value for gestational age (delta value) was computed to allow the casecontrolled comparison of the Em/Am ratio. Expected mean values were derived
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FIGURE 1
Myocardial velocity profile
R ESULTS During the study period, 60 patients with PPROM were admitted to the Obstetrics Department of University of Bari. Twenty-nine patients were excluded because their gestational age on admission was outside the range of 24-34 weeks’ gestation (rupture of membranes occurred at ⬍24 weeks’ gestation in 8 women and at 34-37 weeks’ gestation in 21 women). Of the remaining patients, 4 women did not undergo amniocentesis because of impending preterm delivery, and 15 women were excluded from the study sample because of culture-negative amniotic fluid. Twelve patients met the inclusion criteria; all had agreed to undergo the fetal TDI/SRI echocardiography examination and comprised the study group. The comparison group consisted of 27 healthy fetuses whose mothers were willing to participate in the study over the same period. No patient with an uncomplicated pregnancy who was asked to participate in the research project refused participation. Microorganisms that were isolated from the amniotic cavity of women with PPROM included Mycoplasma hominis (n ⫽ 5), Ureaplasma urealyticum (n ⫽ 3), Candida species (n ⫽ 2), Proteus mirabilis (n ⫽ 1), and Pseudomonas aeruginosa (n ⫽ 1). The mean gestational age at echocardiography assessment was 29.1 ⫾ 6.3 weeks in the comparison group and 29.9 ⫾ 3.2 in patients with PPROM (P ⫽ .69). In the study group, the median latency period (time between PROM and onset of labor) was 4.5 days (range, 0 –17 days). Patients with PPROM delivered considerably earlier (30.8 ⫾ 3.5 weeks vs 38.3 ⫾ 1.3 weeks; P ⬍ .0001) and had neonates with significantly lower birthweight (1728 ⫾ 557 g vs 3199 ⫾ 366 g; P ⬍ .0001) than the comparison patients. Myocardial velocity profile sampled at the right ventricle free wall and the corresponding strain and SR curves of a healthy fetus and of a fetus who was exposed to intraamniotic infection are shown in Figures 1 and 2, respectively.
The top panel is the normal myocardial velocity profile that was sampled at the right ventricle free wall (mid third). The middle panel is the strain rate; note the negative strain rate in systole and the positive strain rate in diastole. The bottom panel shows the corresponding right ventricular strain. A, late diastolic myocardial velocity associated with atrial contraction; E, peak early diastolic myocardial relaxation velocity; S, peak systolic shortening velocity. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
Diastolic function Myocardial tissue velocity could be measured in all 39 fetuses. The difference between the observed and expected value of Em/Am ratio was higher in fetuses with PPROM than in the comparison group (Figure 3). Strain and SR measurements were obtained in all recruited fetuses. SR analysis showed that fetuses with PPROM had a significantly higher peak SR in early diastole than did control subjects (5.7 ⫾ 4.0 sec–1 vs 3.4 ⫾ 2.4 sec–1; P ⫽ .038)
Systolic function Peak systolic strain and SR values are demonstrated graphically in Figure 4. Systolic lengthening of the right ventricle myocardium was observed in 5 fetuses (41.7%) with PPROM, compared with no cases in the comparison group (P ⫽ .001). Isolated histologic chorioamnionitis was diagnosed in 83.3% (10/12) and funisitis was found in 50% (6/12) of fetuses with PPROM, respectively. Whenever funisitis was present, chorioamnionitis was present as well. Figure 5 shows dia-
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FIGURE 2
Myocardial velocity profile, strain, and strain rate of a fetus with preterm premature rupture of membranes
www.AJOG.org (P ⫽ .01). All fetuses with histologic evidence of funisitis exhibited both a peak systolic strain and SR equal to zero or reversed, which indicated systolic lengthening of the myocardium.
C OMMENT
Note: the reversal of the E and A waves (predominance of E wave) on the tissue Doppler imaging velocity curve (top panel ); strain rate close to zero during systole (middle panel ); longitudinal expansion in systole with inverted and positive systolic strain (bottom panel ). A, late diastolic myocardial velocity associated with atrial contraction; E, peak early diastolic myocardial relaxation velocity; S, peak systolic shortening velocity. The first dotted red vertical line represents the time of peak systolic myocardial velocity; the second red line identifies end systole. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
stolic myocardial velocity and systolic strain measurements of the study sample according to the presence or absence of histologic funisitis. Delta Em/Am velocity ratio was significantly higher in fetuses with PPROM who had funisitis than in those with PPROM without funisitis 459.e4
The results of this investigation support the hypothesis that a fraction of fetuses whose mother had a PPROM with proven MIAC exhibits both diastolic and systolic impairment when cardiac function is assessed by direct measurement of myocardial velocity and deformation with TDI/SRI techniques. Application of standard methods of assessment of ventricular function to the fetal heart always has been limited by technical difficulties (because of small cardiac size, lack of direct access to the fetal pericardium, fetal motion, and infinite heart positions in relation to ultrasound beam), inaccuracy, and poor reproducibility. TDI and SRI offer potential advantages over conventional cardiac ultrasound imaging in that they provide quantitative results, they help differentiate myocyte shortening from movement of myocardium as a result of translational motion of the heart or as a result of tethering, and they are less loaddependent than other indices of ventricular function. Romero et al4 previously described impaired diastolic function in fetuses of mothers with PPROM and particularly in cases with intraamniotic infection, compared with the pattern of ventricular filling in normal fetuses. Evaluation of diastolic performance was based on blood inflow velocity profile and changes that were consistent with increased ventricular compliance (higher early-toatrial filling velocity ratio) were demonstrable in the left but not right ventricle. In the current study, we chose to assess right ventricular function because the right ventricle is anatomically and functionally dominant in utero, which contributes to 60% of the total cardiac output. By TDI assessment of diastolic function, we showed aberrant right ventricular relaxation in fetuses with PPROM, as reflected by a higher Em/Am ratio in the study group compared to
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control fetuses. The E/A ratio, a conventional measure of global diastolic function, has been shown to fall with an increase in the number of myocardial segments that exhibit a reduction in the tissue velocity Em/Am ratio, which lends support to the hypothesis that TDI offers a valuable measure of regional diastolic function.12 Moreover, evidence has been provided that diastolic tissue velocities are less influenced by the changes in preload, which commonly compensate for diastolic impairment and which confound assessment by standard measures based on atrioventricular inflow velocity profile.13 The ability of TDI to better recognize more subtle abnormalities in myocyte contractile function may explain the lack of concordance between our findings and the observation by Romero et al4 on the right ventricle function in fetuses with PPROM. Indeed, in the adult patient, myocardial velocities were found to be reduced persistently, even in the early stages of diastolic dysfunction, which was characterized by increased preload compensation and thus normal findings when we relied on standard Doppler criteria alone.14 In addition, Watanabe et al11 demonstrated that, in hydropic fetuses who had heart failure, deterioration of longitudinal left ventricular motion preceded the decrease in right ventricle motion, which remained normal until late in the disease process. This reflected changes in the loading conditions of the ventricles, with a compensatory increased output of the right ventricle that may have confounded measurement of diastolic function by conventional methods. In our study cohort, diastolic function has been further evaluated by strain Doppler echocardiography. Both in animal models and in humans, when the hemodynamic determinants of diastolic Doppler indices of myocardial function were examined, early diastolic SR was related significantly to the time constant of ventricular relaxation and regional stiffness.15,16 Although the velocity profile of atrioventricular inflow provides information on global function, SR provides insight into the rate of diastolic deformation and is less influenced by contractile functions of adjacent myocardial regions
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www.AJOG.org because of tethering. The results of diastolic SR measurements that indicate higher values in PPROM fetuses than in control fetuses further support the concept of increased ventricular relaxation in the setting of intraamniotic infection. The finding of more compliant myocardial walls (a so-called “floppy heart”) is consistent with the ventricular compliance abnormalities that have been described in the adult with sepsis or septic shock.17-19 Indeed, with the use of serial radionuclide cineangiography and echocardiographic evaluation, it was demonstrated that sepsis-induced reduction of ejection fraction was associated with acute ventricular dilation, with an increased end-diastolic volume index that returned to normal over 7-10 days as the patient recovered.17 Notably, survivors of septic shock were more likely to demonstrate acute left ventricular dilation than were nonsurvivors, who typically maintained normal cardiac volumes. Sepsis-induced ventricular dilation is considered to allow maintenance of cardiac output in response to the impairment of systolic ventricular ejection, which suggests that this response to sepsis may convey a positive survival value. The mechanisms by which a previously healthy ventricle can dilate acutely in response to systolic ejection impairment currently are unknown. The results of several investigations have suggested that nitric oxide, a well-recognized myocardial depressant with a multifaceted role in cardiac physiologic condition, may increase ventricular compliance and allow the septic heart to fill more easily during diastole.20 In the current study, strain analysis has been used also to assess regional systolic function of fetuses with PPROM and intraamniotic infection. Measurements of systolic function that have been validated in adults (such as the ejection fraction) often fail to provide accurate results in fetuses because of small ventricular volume that magnify errors in the measurement of ventricular diameters and difficulty in visual borders detection. By direct analysis of deformation and the velocity of deformation over time in small segments of myocardium, SRI may allow a better measure of ven-
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FIGURE 3
Difference between the observed and the expected early diastolic relaxation (Em) and atrial contraction (Am) ratio (delta value)
The closed circles represent patients with uncomplicated pregnancy; the open circles represent patients with preterm premature rupture of membranes and proven microbial invasion of the amniotic cavity. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
tricular contractility. To optimally assess regional myocardial function, both strain and SR must be calculated because they provide complementary informa-
tion: end systolic strain estimates ejection fraction, whereas peak systolic SR is a measure of contractility, as confirmed by analysis of peak elastance. Myocardial
FIGURE 4
Peak systolic strain and strain rate at the right ventricle free wall (mid third)
The closed circles represent patients with uncomplicated pregnancy; the open circles represent patients with preterm premature rupture of membranes and proven microbial invasion of the amniotic cavity. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
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FIGURE 5
The study group according to the presence or absence of histologic funisitis
A, Early diastolic relaxation (Em) and atrial contraction (Am) ratio; B, peak systolic strain rate, and C, strain. The open squares represent patients with preterm premature rupture of membranes and proven microbial invasion of the amniotic cavity (MIAC) without funisitis; the closed squares represent fetuses with histologic evidence of funisitis. S, systolic. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
strain and SR have been validated in vitro with compressed gelatin phantoms and in vivo with ultrasonic crystals, pressure-volume loops, and magnetic resonance imaging before implementation in clinical settings for exploration of systolic function in the adult under various conditions. Systolic strain measurement has been used to investigate myocardial contractile function of normal fetuses with different techniques and to explore different regions of interest, and normal reference ranges have been established. In our study population, regional systolic hypokinesis or akinesis, as reflected by an SRs distribution that indicates a myocardial contractility close to zero or anarchic, was noted more frequently among fetuses with MIAC, in particular those fetuses with funisitis, than among the comparison subjects. Moreover, in most fetuses with funisitis, the histologic counterpart of FIRS21 exhibited paradoxic myocardial movements with longitudinal expansion in systole (inverted and positive peak systolic strain and SR), which suggests dyskinesia of the free wall of the right ventricle. This is in agreement with studies of patients with septic shock, which report wall motion abnormalities in 45% of the subjects, although the prevalent cardiac dysfunction that was observed was global akinesia.22,23 Various mechanisms can explain the development of septic myocardial de459.e6
pression, most of which are regulated by cytokines and inflammatory pathways that are also involved in FIRS.24,25 However, the importance and hierarchy of these mechanisms in sepsis-induced organ dysfunction have not been elucidated yet. It has been suggested that myocardial depression could protect the heart by reducing cellular energy expenditure in a situation in which energy generation is impaired because of mitochondrial dysfunction and circulatory abnormalities, thereby preventing activation of cell death pathways and allowing the potential for full functional recovery.26 This hypothesis merits further investigation because it may carry major implications in our understanding of the pathophysiologic elements of FIRS and ultimately for the clinical treatment of our patients. Consistent with our findings is the association between histologic chorioamnionitis and elevated cord blood interleukin-6 concentrations and disturbances in cardiac function and systemic hemodynamic that were observed in premature infants by Yanowitz et al.27 It has been speculated that these hemodynamic changes, which include a decreased mean and diastolic blood pressure, could be present in utero also and may predispose such fetuses to perinatal brain injury. Indeed, there is accumulating evidence that the brain of the sick preterm
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infant often shows impaired cerebrovascular autoregulation and therefore may be highly vulnerable to even minor decreases in systemic blood pressure.28 Extraordinary insights into the pathogenesis of cerebral white matter injury in recent years indicate that ischemia (most likely resulting from systemic hypotension and pressure-passive cerebral circulation) and inflammation may act in concert to potentiate each other and lead to the death of premyelinating oligodendrocytes in the preterm brain. On the whole, our results indicate that fetuses with PPROM and proven MIAC exhibit impairment in both diastolic and systolic performance, which is characterized by increased diastolic compliance (increased Em/Am ratio, increased early diastolic SR), decreased systolic contractile function (reduced SRs), and longitudinal myocardial dyskinesia. This profile closely resembles the pattern of sepsisinduced myocardial dysfunction in the adult patients. Our pioneer work must be confirmed by future reports for a better understanding of myocardial involvement in the context of FIRS. As we continue to grow in our understanding of the pathogenesis and hemodynamics of FIRS, the hope is that continued investigation will lead to new management strategies and possibly to therapeutic options. f
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www.AJOG.org REFERENCES 1. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194-202. 2. Yoon BH, Jun JK, Romero R, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997;177: 19-26. 3. Yoon BH, Romero R, Moon JB, et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2001;185: 1130-6. 4. Romero R, Espinoza J, Goncalves LF, et al. Fetal cardiac dysfunction in preterm premature rupture of membranes. J Matern Fetal Neonatal Med 2004;16:146-57. 5. Harada K, Tsuda A, Orino T, Tanaka T, Takada G. Tissue Doppler imaging in the normal fetus. Int J Cardiol 1999 ;71:227-34. 6. Aoki M, Harada K, Ogawa M, Tanaka T. Quantitative assessment of right ventricular function using Doppler tissue imaging in fetuses with and without heart failure. J Am Soc Echocardiogr 2004;17:28-35. 7. Gardiner HM, Pasquini L, Wolfenden J, et al. Myocardial tissue Doppler and long axis function in the fetal heart. Int J Cardiol 2006; 113:39-47. 8. Larsen LU, Petersen OB, Norrild K, Sorensen K, Uldbjerg N, Sloth E. Strain rate derived from color Doppler myocardial imaging for assessment of fetal cardiac function. Ultrasound Obstet Gynecol 2006;27:210-3. 9. Perles Z, Nir A, Gavri S, Rein AJ. Assessment of fetal myocardial performance using myocardial deformation analysis. Am J Cardiol 2007;99:993-6.
10. Di Salvo G, Russo MG, Paladini D, et al. Two-dimensional strain to assess regional left and right ventricular longitudinal function in 100 normal foetuses. Eur J Echocardiogr 2008; 9:754-6. 11. Watanabe S, Hashimoto I, Saito K, et al. Characterization of ventricular myocardial performance in the fetus by tissue Doppler imaging. Circ J 2009;73:943-7. 12. Garcia-Fernandez MA, Azevedo J, Moreno M, Bermejo J, Moreno R. Regional left ventricular diastolic dysfunction evaluated by pulsedtissue Doppler echocardiography. Echocardiography 1999;16:491-500. 13. Farias CA, Rodriguez L, Garcia MJ, Sun JP, Klein AL, Thomas JD. Assessment of diastolic function by tissue Doppler echocardiography: comparison with standard transmitral and pulmonary venous flow. J Am Soc Echocardiogr 1999;12:609-17. 14. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865-75. 15. Pislaru C, Bruce CJ, Anagnostopoulos PC, et al. Ultrasound strain imaging of altered myocardial stiffness: stunned versus infarcted reperfused myocardium. Circulation 200;109: 2905-10. 16. Park TH, Nagueh SF, Khoury DS, et al. Impact of myocardial structure and function postinfarction on diastolic strain measurements: implications for assessment of myocardial viability. Am J Physiol Heart Circ Physiol 2006;290:H724-31. 17. Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984;100:483-90. 18. Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular dysfunction and dilatation, similar to left ventricular changes, char-
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acterize the cardiac depression of septic shock in humans. Chest 1990;97:126-31. 19. Bouhemad B, Nicolas-Robin A, Arbelot C, Arthaud M, Fèger F, Rouby JJ. Acute left ventricular dilatation and shock-induced myocardial dysfunction. Crit Care Med 2009;37: 441-7. 20. Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans: assessment by bicoronary sodium nitroprusside infusion. Circulation 1994;89:2070-8. 21. Pacora P, Chaiworapongsa T, Maymon E, et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med 2002;11:18-25. 22. Chidiac TA, Salon JE. Left ventricular segmental wall motion abnormality in septic shock. Crit Care Med 1995;23:594-8. 23. Vieillard-Baron A, Caille V, Charron C, Belliard G, Page B, Jardin F. Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 2008;36:1701-6. 24. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 2007;35:1599-608. 25. Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth 2010;104:3-11. 26. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 2005;288:H984-99. 27. Yanowitz TD, Jordan JA, Gilmour CH, et al. Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res 2002;51:310-6. 28. Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 2008;93:F153-61.
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OBSTETRICS
Myocardial dysfunction in fetuses exposed to intraamniotic infection: new insights from tissue Doppler and strain imaging Edoardo Di Naro, MD; Antonella Cromi, PhD; Fabio Ghezzi, MD; Alessandra Giocolano, MD; Annamaria Caringella, MD; Giuseppe Loverro, MD OBJECTIVE: The purpose of this study was to assess myocardial func-
RESULTS: Fetuses with intraamniotic infection exhibit impairment in both
tion of fetuses who were exposed to intraamniotic infection compared with fetuses of uncomplicated pregnancies by the application of tissue Doppler and strain rate (SR) imaging.
diastolic and systolic performance, which was characterized by increased diastolic compliance (increased Em/Am ratio, increased early diastolic SR compared with the control fetuses), decreased systolic contractile function (reduced systolic strain and SR), and longitudinal myocardial dyskinesia.
STUDY DESIGN: We evaluated the right ventricular function of fetuses
with preterm premature rupture of membranes and proven intraamniotic infection (n ⫽ 12 fetuses) and healthy fetuses (n ⫽ 27). Tissue Doppler velocities during early diastolic relaxation (Em) and atrial contraction (Am) and early diastolic SR were measured as indices of diastolic function, whereas the peak systolic strain and SR were used as parameters of systolic function.
CONCLUSION: New echocardiographic tools suggest that fetal heart is
a target organ in the context of intraamniotic infection. Key words: fetal heart, fetal inflammatory response syndrome, intraamniotic infection, myocardium, preterm, strain, tissue Doppler imaging
Cite this article as: Di Naro E, Cromi A, Ghezzi F, et al. Myocardial dysfunction in fetuses exposed to intraamniotic infection: new insights from tissue Doppler and strain imaging. Am J Obstet Gynecol 2010;203:459.e1-7.
T
he term fetal inflammatory response syndrome (FIRS) was coined for the first time in 1997 to indicate the fetal counterpart of the systemic inflammatory response syndrome (SIRS) that originally was described in adults.1 SIRS results from the systemic response of the body to infection and is characterized by activation and amplification of various proinflammatory and antiinflammatory
From the Department of Obstetrics and Gynecology, University of Insubria, Varese (Drs Cromi and Ghezzi), and the Third Department of Obstetrics and Gynecology, University of Bari, Bari (Drs Di Naro, Giocolano, Caringella, and Loverro), Italy. Received March 1, 2010; revised May 2, 2010; accepted June 15, 2010. Reprints: Edoardo Di Naro, MD, Department of Obstetrics and Gynecology, University of Bari, Ospedale Consorziale Policlinico, Piazza Giulio Cesare, 70100 Bari, Italy. [email protected]. Authorship and contribution to the article is limited to the 6 authors indicated. There was no outside funding or technical assistance with the production of this article. 0002-9378/$36.00 © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.06.033
pathways. The effects of these overwhelming pro- and antiinflammatory stimuli culminate with the progressive and sequential dysfunction of several organ systems that range from a mild degree of physiologic derangement in individual organs to frank multiple organ failure and ultimately death. Myocardial depression is a well-recognized manifestation of organ dysfunction in SIRS and accounts for much of the associated morbidity and mortality rates. FIRS occurs in a fraction of fetuses who are exposed to intraamniotic infection and is associated with impending preterm delivery, higher risk of perinatal death, serious neonatal morbidity, and long-term sequelae.2,3 Despite differences in fetal and adult immune systems, FIRS demonstrates a substantial degree of similarity with SIRS/sepsis both in underlying molecular mechanisms and in clinical patterns, which include progression toward multisystem organ involvement. Similar to adult syndrome, fetal heart has been suggested to be a target organ during FIRS, and cardiac diastolic dysfunction has been detected by conventional Doppler examination of intracardiac blood flow velocities in fetuses with preterm premature rupture of
membranes (PPROM), particularly in those fetuses with a proven intraamniotic infection.4 Over the last 10 years, technologic advances in signal processing made it possible to measure directly myocardial wall motion velocity, the magnitude of tissue deformation (myocardial strain), and the rate at which deformation occurs (strain rate [SR]), which has provided information on myocardial properties and mechanics that would otherwise be unavailable. In the adult, assessment of diastolic and systolic function by analysis of tissue Doppler velocity data, strain, and SR has been validated extensively. Application of tissue Doppler imaging (TDI) and SR imaging (SRI) to the fetus with and without heart disease has been reported only in recent times,5-11 and such tools have emerged by promising to quantify fetal cardiac function objectively and accurately, which is an objective that has long been considered almost elusive. TDI- and SRI-derived parameters have not been used so far for the assessment of fetal cardiac performance in the context of intrauterine infection/inflammation. Thus, we designed this study to assess myocardial function of fetuses of women
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with PPROM and proven microbial invasion of the amniotic cavity (MIAC), compared with fetuses of women with uncomplicated pregnancies, by applying echocardiographic measurement of tissue velocity, strain, and SR.
M ATERIALS AND M ETHODS Patient population The study population consisted of fetuses whose mothers were admitted between April 2007 and September 2009 with the diagnosis of PPROM between 24 and 34 weeks of gestation and who were offered amniocentesis for the evaluation of the microbial status of the amniotic cavity. Inclusion criteria were (1) singleton gestation, (2) certain gestational age, (3) absence of chromosomal abnormality or congenital malformations detected pre- or postnatally, (4) estimated fetal weight on ultrasound ⬎10th percentile, and (5) microbiologically proven intraamniotic infection (positive amniotic fluid culture). The diagnosis of PPROM was supported by the detection of a pool of fluid in the posterior vaginal fornix on sterile speculum examination and was confirmed by Nitrazine testing for an alkaline pH. Tocolytic agents, antibiotics, and steroids were not administered before maternal blood and amniotic fluid were collected. Calculation of gestational age was based on reliable recollection of the last menstrual period and confirmed or modified by ultrasound scans within the first 14 weeks of gestation. The comparison group consisted of fetuses whose mothers had an uncomplicated pregnancy and were referred for fetal echocardiography. Indications for referral were related to family history of congenital heart anomaly or suspected arrhythmia that had been ruled out. We excluded fetuses of mothers with systemic diseases, such as maternal diabetes mellitus or systemic lupus erythematosus, and fetuses with chromosomal or any other congenital anomaly. Anthropometric parameters were measured in all fetuses to rule out the possibility of growth restriction. We decided to enroll at least 2 healthy control fetuses per case; we prolonged enrollment until the de459.e2
www.AJOG.org sired number of study subjects was achieved. The study was approved by the Institutional Review Board Committee of University of Bari. Written informed consent was obtained from all the participants.
Sonographic evaluation The ultrasound examinations were performed with an Aloka ProSound Alpha 10 (Aloka, Tokyo, Japan), which was equipped with a phased-array duplex multifrequency transducer. All participating patients underwent a full morphologic examination of the fetal heart before quantitative assessment of right ventricular function with TDI and SRI techniques. A single investigator (E.D.N.) performed all fetal echocardiography studies. For each fetus, a highresolution, zoomed loop of the apical 4-chamber view that incorporated at least 3 complete cardiac cycles was recorded. A narrow sector angle was used, and image depth was adjusted to allow for a maximal acquisition frame rate. Special care was taken to align the interventricular septum with the ultrasound beam (angulation, ⬍30 degrees), and no angle correction was carried out. Digital loops were transferred to a dedicated workstation for offline analysis. Longitudinal segmental contraction and relaxation velocities of the right ventricle myocardium and strain and SR measurements were obtained by the technique described by Perles et al.9 Briefly, myocardial velocity profile was recorded by placement of the region of interest in the basal portion of the right free ventricular wall, adjacent to the tricuspid annulus. For strain and SR analysis, the region of interest was selected in the mid onethird of the right ventricle free wall. Through spatial derivation of the velocity data along the myocardial section of interest, Doppler-derived SR can be obtained. Further temporal integration of the SR will extract Doppler-derived strain. Two-dimensional echocardiography was used to record aortic valve closure and atrioventicular valves opening and closure, which were used for timing events during the cardiac cycle. By convention, strain is defined as positive when the distance between the points of
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measurements is increasing (ie, lengthening); shortening is represented by negative strain. Correspondingly, normal ventricular myocardium has a negative SR in systole and a positive SR during diastole. The following parameters were measured and averaged over 3 cycles: tissue Doppler velocities during early diastolic relaxation (Em) and atrial contraction (Am) and early diastolic SRs, as indices of right ventricle diastolic function and the peak systolic strain and SR as parameters of systolic function. Em/Am ratio was calculated as a surrogate measure of overall diastolic function.
Specimen collection and histologic examination In the study group, amniocentesis was performed with a 21-gauge needle under ultrasonographic guidance with a freehand technique. A sample of amniotic fluid was sent to the laboratory in a capped syringe immediately after collection for white blood cell count determination and cultures. Amniotic fluid was cultured for aerobic and anaerobic bacteria and for Mycoplasmas. At delivery, tissue samples were obtained from the umbilical cord and placenta. Histologic chorioamnionitis was defined as the presence of acute inflammatory changes in any of the placental tissue samples (amnion, chorion-decidua, and chorionic plate). Funisitis was diagnosed in the presence of neutrophilic infiltration in the umbilical cord wall vessels or in the Wharton’s jelly. Statistical analysis Statistical analysis was performed with GraphPad Prism (version 5.0c for Macintosh; GraphPad Software, San Diego CA). The t test and the Mann Whitney U test were used to compare continuous parametric and nonparametric variables, respectively. Proportions were analyzed with Fisher’s exact test. Because myocardial tissue velocity increases as a function of gestational age, the difference between the observed value and the mean value for gestational age (delta value) was computed to allow the casecontrolled comparison of the Em/Am ratio. Expected mean values were derived
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FIGURE 1
Myocardial velocity profile
R ESULTS During the study period, 60 patients with PPROM were admitted to the Obstetrics Department of University of Bari. Twenty-nine patients were excluded because their gestational age on admission was outside the range of 24-34 weeks’ gestation (rupture of membranes occurred at ⬍24 weeks’ gestation in 8 women and at 34-37 weeks’ gestation in 21 women). Of the remaining patients, 4 women did not undergo amniocentesis because of impending preterm delivery, and 15 women were excluded from the study sample because of culture-negative amniotic fluid. Twelve patients met the inclusion criteria; all had agreed to undergo the fetal TDI/SRI echocardiography examination and comprised the study group. The comparison group consisted of 27 healthy fetuses whose mothers were willing to participate in the study over the same period. No patient with an uncomplicated pregnancy who was asked to participate in the research project refused participation. Microorganisms that were isolated from the amniotic cavity of women with PPROM included Mycoplasma hominis (n ⫽ 5), Ureaplasma urealyticum (n ⫽ 3), Candida species (n ⫽ 2), Proteus mirabilis (n ⫽ 1), and Pseudomonas aeruginosa (n ⫽ 1). The mean gestational age at echocardiography assessment was 29.1 ⫾ 6.3 weeks in the comparison group and 29.9 ⫾ 3.2 in patients with PPROM (P ⫽ .69). In the study group, the median latency period (time between PROM and onset of labor) was 4.5 days (range, 0 –17 days). Patients with PPROM delivered considerably earlier (30.8 ⫾ 3.5 weeks vs 38.3 ⫾ 1.3 weeks; P ⬍ .0001) and had neonates with significantly lower birthweight (1728 ⫾ 557 g vs 3199 ⫾ 366 g; P ⬍ .0001) than the comparison patients. Myocardial velocity profile sampled at the right ventricle free wall and the corresponding strain and SR curves of a healthy fetus and of a fetus who was exposed to intraamniotic infection are shown in Figures 1 and 2, respectively.
The top panel is the normal myocardial velocity profile that was sampled at the right ventricle free wall (mid third). The middle panel is the strain rate; note the negative strain rate in systole and the positive strain rate in diastole. The bottom panel shows the corresponding right ventricular strain. A, late diastolic myocardial velocity associated with atrial contraction; E, peak early diastolic myocardial relaxation velocity; S, peak systolic shortening velocity. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
Diastolic function Myocardial tissue velocity could be measured in all 39 fetuses. The difference between the observed and expected value of Em/Am ratio was higher in fetuses with PPROM than in the comparison group (Figure 3). Strain and SR measurements were obtained in all recruited fetuses. SR analysis showed that fetuses with PPROM had a significantly higher peak SR in early diastole than did control subjects (5.7 ⫾ 4.0 sec–1 vs 3.4 ⫾ 2.4 sec–1; P ⫽ .038)
Systolic function Peak systolic strain and SR values are demonstrated graphically in Figure 4. Systolic lengthening of the right ventricle myocardium was observed in 5 fetuses (41.7%) with PPROM, compared with no cases in the comparison group (P ⫽ .001). Isolated histologic chorioamnionitis was diagnosed in 83.3% (10/12) and funisitis was found in 50% (6/12) of fetuses with PPROM, respectively. Whenever funisitis was present, chorioamnionitis was present as well. Figure 5 shows dia-
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FIGURE 2
Myocardial velocity profile, strain, and strain rate of a fetus with preterm premature rupture of membranes
www.AJOG.org (P ⫽ .01). All fetuses with histologic evidence of funisitis exhibited both a peak systolic strain and SR equal to zero or reversed, which indicated systolic lengthening of the myocardium.
C OMMENT
Note: the reversal of the E and A waves (predominance of E wave) on the tissue Doppler imaging velocity curve (top panel ); strain rate close to zero during systole (middle panel ); longitudinal expansion in systole with inverted and positive systolic strain (bottom panel ). A, late diastolic myocardial velocity associated with atrial contraction; E, peak early diastolic myocardial relaxation velocity; S, peak systolic shortening velocity. The first dotted red vertical line represents the time of peak systolic myocardial velocity; the second red line identifies end systole. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
stolic myocardial velocity and systolic strain measurements of the study sample according to the presence or absence of histologic funisitis. Delta Em/Am velocity ratio was significantly higher in fetuses with PPROM who had funisitis than in those with PPROM without funisitis 459.e4
The results of this investigation support the hypothesis that a fraction of fetuses whose mother had a PPROM with proven MIAC exhibits both diastolic and systolic impairment when cardiac function is assessed by direct measurement of myocardial velocity and deformation with TDI/SRI techniques. Application of standard methods of assessment of ventricular function to the fetal heart always has been limited by technical difficulties (because of small cardiac size, lack of direct access to the fetal pericardium, fetal motion, and infinite heart positions in relation to ultrasound beam), inaccuracy, and poor reproducibility. TDI and SRI offer potential advantages over conventional cardiac ultrasound imaging in that they provide quantitative results, they help differentiate myocyte shortening from movement of myocardium as a result of translational motion of the heart or as a result of tethering, and they are less loaddependent than other indices of ventricular function. Romero et al4 previously described impaired diastolic function in fetuses of mothers with PPROM and particularly in cases with intraamniotic infection, compared with the pattern of ventricular filling in normal fetuses. Evaluation of diastolic performance was based on blood inflow velocity profile and changes that were consistent with increased ventricular compliance (higher early-toatrial filling velocity ratio) were demonstrable in the left but not right ventricle. In the current study, we chose to assess right ventricular function because the right ventricle is anatomically and functionally dominant in utero, which contributes to 60% of the total cardiac output. By TDI assessment of diastolic function, we showed aberrant right ventricular relaxation in fetuses with PPROM, as reflected by a higher Em/Am ratio in the study group compared to
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control fetuses. The E/A ratio, a conventional measure of global diastolic function, has been shown to fall with an increase in the number of myocardial segments that exhibit a reduction in the tissue velocity Em/Am ratio, which lends support to the hypothesis that TDI offers a valuable measure of regional diastolic function.12 Moreover, evidence has been provided that diastolic tissue velocities are less influenced by the changes in preload, which commonly compensate for diastolic impairment and which confound assessment by standard measures based on atrioventricular inflow velocity profile.13 The ability of TDI to better recognize more subtle abnormalities in myocyte contractile function may explain the lack of concordance between our findings and the observation by Romero et al4 on the right ventricle function in fetuses with PPROM. Indeed, in the adult patient, myocardial velocities were found to be reduced persistently, even in the early stages of diastolic dysfunction, which was characterized by increased preload compensation and thus normal findings when we relied on standard Doppler criteria alone.14 In addition, Watanabe et al11 demonstrated that, in hydropic fetuses who had heart failure, deterioration of longitudinal left ventricular motion preceded the decrease in right ventricle motion, which remained normal until late in the disease process. This reflected changes in the loading conditions of the ventricles, with a compensatory increased output of the right ventricle that may have confounded measurement of diastolic function by conventional methods. In our study cohort, diastolic function has been further evaluated by strain Doppler echocardiography. Both in animal models and in humans, when the hemodynamic determinants of diastolic Doppler indices of myocardial function were examined, early diastolic SR was related significantly to the time constant of ventricular relaxation and regional stiffness.15,16 Although the velocity profile of atrioventricular inflow provides information on global function, SR provides insight into the rate of diastolic deformation and is less influenced by contractile functions of adjacent myocardial regions
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www.AJOG.org because of tethering. The results of diastolic SR measurements that indicate higher values in PPROM fetuses than in control fetuses further support the concept of increased ventricular relaxation in the setting of intraamniotic infection. The finding of more compliant myocardial walls (a so-called “floppy heart”) is consistent with the ventricular compliance abnormalities that have been described in the adult with sepsis or septic shock.17-19 Indeed, with the use of serial radionuclide cineangiography and echocardiographic evaluation, it was demonstrated that sepsis-induced reduction of ejection fraction was associated with acute ventricular dilation, with an increased end-diastolic volume index that returned to normal over 7-10 days as the patient recovered.17 Notably, survivors of septic shock were more likely to demonstrate acute left ventricular dilation than were nonsurvivors, who typically maintained normal cardiac volumes. Sepsis-induced ventricular dilation is considered to allow maintenance of cardiac output in response to the impairment of systolic ventricular ejection, which suggests that this response to sepsis may convey a positive survival value. The mechanisms by which a previously healthy ventricle can dilate acutely in response to systolic ejection impairment currently are unknown. The results of several investigations have suggested that nitric oxide, a well-recognized myocardial depressant with a multifaceted role in cardiac physiologic condition, may increase ventricular compliance and allow the septic heart to fill more easily during diastole.20 In the current study, strain analysis has been used also to assess regional systolic function of fetuses with PPROM and intraamniotic infection. Measurements of systolic function that have been validated in adults (such as the ejection fraction) often fail to provide accurate results in fetuses because of small ventricular volume that magnify errors in the measurement of ventricular diameters and difficulty in visual borders detection. By direct analysis of deformation and the velocity of deformation over time in small segments of myocardium, SRI may allow a better measure of ven-
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FIGURE 3
Difference between the observed and the expected early diastolic relaxation (Em) and atrial contraction (Am) ratio (delta value)
The closed circles represent patients with uncomplicated pregnancy; the open circles represent patients with preterm premature rupture of membranes and proven microbial invasion of the amniotic cavity. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
tricular contractility. To optimally assess regional myocardial function, both strain and SR must be calculated because they provide complementary informa-
tion: end systolic strain estimates ejection fraction, whereas peak systolic SR is a measure of contractility, as confirmed by analysis of peak elastance. Myocardial
FIGURE 4
Peak systolic strain and strain rate at the right ventricle free wall (mid third)
The closed circles represent patients with uncomplicated pregnancy; the open circles represent patients with preterm premature rupture of membranes and proven microbial invasion of the amniotic cavity. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
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FIGURE 5
The study group according to the presence or absence of histologic funisitis
A, Early diastolic relaxation (Em) and atrial contraction (Am) ratio; B, peak systolic strain rate, and C, strain. The open squares represent patients with preterm premature rupture of membranes and proven microbial invasion of the amniotic cavity (MIAC) without funisitis; the closed squares represent fetuses with histologic evidence of funisitis. S, systolic. Di Naro. Cardiac dysfunction in preterm PROM. Am J Obstet Gynecol 2010.
strain and SR have been validated in vitro with compressed gelatin phantoms and in vivo with ultrasonic crystals, pressure-volume loops, and magnetic resonance imaging before implementation in clinical settings for exploration of systolic function in the adult under various conditions. Systolic strain measurement has been used to investigate myocardial contractile function of normal fetuses with different techniques and to explore different regions of interest, and normal reference ranges have been established. In our study population, regional systolic hypokinesis or akinesis, as reflected by an SRs distribution that indicates a myocardial contractility close to zero or anarchic, was noted more frequently among fetuses with MIAC, in particular those fetuses with funisitis, than among the comparison subjects. Moreover, in most fetuses with funisitis, the histologic counterpart of FIRS21 exhibited paradoxic myocardial movements with longitudinal expansion in systole (inverted and positive peak systolic strain and SR), which suggests dyskinesia of the free wall of the right ventricle. This is in agreement with studies of patients with septic shock, which report wall motion abnormalities in 45% of the subjects, although the prevalent cardiac dysfunction that was observed was global akinesia.22,23 Various mechanisms can explain the development of septic myocardial de459.e6
pression, most of which are regulated by cytokines and inflammatory pathways that are also involved in FIRS.24,25 However, the importance and hierarchy of these mechanisms in sepsis-induced organ dysfunction have not been elucidated yet. It has been suggested that myocardial depression could protect the heart by reducing cellular energy expenditure in a situation in which energy generation is impaired because of mitochondrial dysfunction and circulatory abnormalities, thereby preventing activation of cell death pathways and allowing the potential for full functional recovery.26 This hypothesis merits further investigation because it may carry major implications in our understanding of the pathophysiologic elements of FIRS and ultimately for the clinical treatment of our patients. Consistent with our findings is the association between histologic chorioamnionitis and elevated cord blood interleukin-6 concentrations and disturbances in cardiac function and systemic hemodynamic that were observed in premature infants by Yanowitz et al.27 It has been speculated that these hemodynamic changes, which include a decreased mean and diastolic blood pressure, could be present in utero also and may predispose such fetuses to perinatal brain injury. Indeed, there is accumulating evidence that the brain of the sick preterm
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infant often shows impaired cerebrovascular autoregulation and therefore may be highly vulnerable to even minor decreases in systemic blood pressure.28 Extraordinary insights into the pathogenesis of cerebral white matter injury in recent years indicate that ischemia (most likely resulting from systemic hypotension and pressure-passive cerebral circulation) and inflammation may act in concert to potentiate each other and lead to the death of premyelinating oligodendrocytes in the preterm brain. On the whole, our results indicate that fetuses with PPROM and proven MIAC exhibit impairment in both diastolic and systolic performance, which is characterized by increased diastolic compliance (increased Em/Am ratio, increased early diastolic SR), decreased systolic contractile function (reduced SRs), and longitudinal myocardial dyskinesia. This profile closely resembles the pattern of sepsisinduced myocardial dysfunction in the adult patients. Our pioneer work must be confirmed by future reports for a better understanding of myocardial involvement in the context of FIRS. As we continue to grow in our understanding of the pathogenesis and hemodynamics of FIRS, the hope is that continued investigation will lead to new management strategies and possibly to therapeutic options. f
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www.AJOG.org REFERENCES 1. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194-202. 2. Yoon BH, Jun JK, Romero R, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997;177: 19-26. 3. Yoon BH, Romero R, Moon JB, et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2001;185: 1130-6. 4. Romero R, Espinoza J, Goncalves LF, et al. Fetal cardiac dysfunction in preterm premature rupture of membranes. J Matern Fetal Neonatal Med 2004;16:146-57. 5. Harada K, Tsuda A, Orino T, Tanaka T, Takada G. Tissue Doppler imaging in the normal fetus. Int J Cardiol 1999 ;71:227-34. 6. Aoki M, Harada K, Ogawa M, Tanaka T. Quantitative assessment of right ventricular function using Doppler tissue imaging in fetuses with and without heart failure. J Am Soc Echocardiogr 2004;17:28-35. 7. Gardiner HM, Pasquini L, Wolfenden J, et al. Myocardial tissue Doppler and long axis function in the fetal heart. Int J Cardiol 2006; 113:39-47. 8. Larsen LU, Petersen OB, Norrild K, Sorensen K, Uldbjerg N, Sloth E. Strain rate derived from color Doppler myocardial imaging for assessment of fetal cardiac function. Ultrasound Obstet Gynecol 2006;27:210-3. 9. Perles Z, Nir A, Gavri S, Rein AJ. Assessment of fetal myocardial performance using myocardial deformation analysis. Am J Cardiol 2007;99:993-6.
10. Di Salvo G, Russo MG, Paladini D, et al. Two-dimensional strain to assess regional left and right ventricular longitudinal function in 100 normal foetuses. Eur J Echocardiogr 2008; 9:754-6. 11. Watanabe S, Hashimoto I, Saito K, et al. Characterization of ventricular myocardial performance in the fetus by tissue Doppler imaging. Circ J 2009;73:943-7. 12. Garcia-Fernandez MA, Azevedo J, Moreno M, Bermejo J, Moreno R. Regional left ventricular diastolic dysfunction evaluated by pulsedtissue Doppler echocardiography. Echocardiography 1999;16:491-500. 13. Farias CA, Rodriguez L, Garcia MJ, Sun JP, Klein AL, Thomas JD. Assessment of diastolic function by tissue Doppler echocardiography: comparison with standard transmitral and pulmonary venous flow. J Am Soc Echocardiogr 1999;12:609-17. 14. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32:865-75. 15. Pislaru C, Bruce CJ, Anagnostopoulos PC, et al. Ultrasound strain imaging of altered myocardial stiffness: stunned versus infarcted reperfused myocardium. Circulation 200;109: 2905-10. 16. Park TH, Nagueh SF, Khoury DS, et al. Impact of myocardial structure and function postinfarction on diastolic strain measurements: implications for assessment of myocardial viability. Am J Physiol Heart Circ Physiol 2006;290:H724-31. 17. Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984;100:483-90. 18. Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular dysfunction and dilatation, similar to left ventricular changes, char-
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acterize the cardiac depression of septic shock in humans. Chest 1990;97:126-31. 19. Bouhemad B, Nicolas-Robin A, Arbelot C, Arthaud M, Fèger F, Rouby JJ. Acute left ventricular dilatation and shock-induced myocardial dysfunction. Crit Care Med 2009;37: 441-7. 20. Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans: assessment by bicoronary sodium nitroprusside infusion. Circulation 1994;89:2070-8. 21. Pacora P, Chaiworapongsa T, Maymon E, et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med 2002;11:18-25. 22. Chidiac TA, Salon JE. Left ventricular segmental wall motion abnormality in septic shock. Crit Care Med 1995;23:594-8. 23. Vieillard-Baron A, Caille V, Charron C, Belliard G, Page B, Jardin F. Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 2008;36:1701-6. 24. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 2007;35:1599-608. 25. Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth 2010;104:3-11. 26. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 2005;288:H984-99. 27. Yanowitz TD, Jordan JA, Gilmour CH, et al. Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res 2002;51:310-6. 28. Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 2008;93:F153-61.
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