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Myocardial hypertrophy and dysfunction in maternal diabetes
Early Human Development 88 (2012) 273–278
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Best practice guidelines
Myocardial hypertrophy and dysfunction in maternal diabetes Paulo Zielinsky ⁎, Antonio Luiz Piccoli Jr. ⁎⁎ Fetal Cardiology Unit, Institute of Cardiology, Porto Alegre, Brazil
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Keywords: Fetal heart Fetal cardiac function Fetal diastolic dysfunction Diabetes in pregnancy
a b s t r a c t Diabetes in pregnancy, both pre-gestational and gestational, is a frequent cause of fetal myocardial hypertrophy, partly due to fetal hyperinsulinism. In fetal life, cardiac function may be impaired, especially during diastole, as a result of decreased left ventricular distensibility and altered left atrial dynamics secondary to myocardial hypertrophy. In neonates, the hypertrophy is a transient disorder, with spontaneous regression of the increased myocardial thickness during the first months of life. Nevertheless, cardiac hypertrophy may be associated with neonatal cardiomegaly and respiratory distress secondary to poor left ventricular compliance. The development of a number of new echocardiographic parameters discussed in this article, and primarily based on the pathophysiological consequences of myocardial hypertrophy, highlight an area of research priority: the assessment of diastolic function in fetuses of diabetic mothers with (and without) myocardial hypertrophy. A score for grading the severity of fetal diastolic dysfunction in these fetuses is proposed. © 2012 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Myocardial hypertrophy in fetuses of diabetic mothers . . . . . . . . Conventional Doppler assessment of ventricular diastolic function . . . Alternative and newer methods to assess ventricular diastolic function 4.1. Mobility of the septum primum . . . . . . . . . . . . . . . . 4.2. Left atrial shortening fraction (LASF) . . . . . . . . . . . . . 4.3. Impedance to foramen ovale flow . . . . . . . . . . . . . . . 4.4. Impedance to pulmonary venous flow . . . . . . . . . . . . 4.5. Impedance to ductus venosus flow . . . . . . . . . . . . . . 4.6. Fetal ventricular diastolic function assessed by tissue Doppler . 4.7. Fetal aortic isthmus flow index (AIFI) . . . . . . . . . . . . . 5. Ongoing studies on fetal diastolic function in maternal diabetes . . . . 5.1. Left ventricular isovolumic relaxation time in the fetus. . . . . 6. Key guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Future research directions . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Pre-gestational maternal diabetes is a risk factor for fetal structural heart disease. However, fetal cardiac function may be impaired as
⁎ Correspondence to: P. Zielinsky, Av. Cristóvão Colombo 3038 ap. 303, 90560-002 Porto Alegre, RS, Brazil. Tel.: + 55 51 99696227; fax: + 55 51 30619997. ⁎⁎ Correspondence to: A.L. Piccoli Jr, Av. Princesa Isabel 395, 90620-001 Porto Alegre, RS, Brazil. Tel.: + 55 51 98182593; fax: + 55 51 30619997. E-mail addresses: [email protected] (P. Zielinsky), [email protected] (A.L. Piccoli). 0378-3782/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2012.02.006
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a result of myocardial hypertophy, which is prevalent in both gestational and pre-gestational diabetic pregnancies. Post-natally, the increased myocardial thickness (often referred to as ‘diabetic hypertrophic cardiomyopathy’) is transient, with spontaneous regression during the first months of life. Despite this transient nature, neonates of diabetic mothers may present with cardiomegaly and respiratory distress, the latter secondary to poor left ventricular compliance. These findings stress the need for adequate prenatal assessment of diastolic function. In the fetus of diabetic mothers with myocardial hypertrophy, cardiac function may be impaired, especially during diastole, as a
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result of a decreased left ventricular distensibility and altered left atrial dynamics secondary to myocardial hypertrophy. Assessment of diastolic function in these fetuses has become an area of priority for research due to the development of a number of new echocardiographic parameters, which are reviewed in this article.
been found [2]. On the other hand, the increase in septal thickness throughout pregnancy is associated with increased levels of insulin growth factor-1. Fetal cardiac function is also reduced when preconceptual maternal glycated hemoglobin is increased [13]. 3. Conventional Doppler assessment of ventricular diastolic function
2. Myocardial hypertrophy in fetuses of diabetic mothers The most frequent cause of myocardial hypertrophy seen prenatally is observed in fetuses of diabetic mothers. It occurs as a complication of gestational or previous maternal diabetes in about 25–30% of cases [1]. The ventricular septum is preferentially affected, but both right and left ventricular free walls may be involved, predominantly the left [2] (Fig. 1). In-utero manifestation of myocardial hypertrophy is often not striking, but the hypertrophy is easily detected by standard fetal echocardiography, usually by comparing septal thickness with established nomograms [3,4]. Septal thickness greater than two standard deviations for gestational age is considered abnormal. Histological features include increased nuclear and sarcolemmal mass, as well as vacuolization and hydrops of hyperplastic myocardial cells [5–7]. The etiology of myocardial hypertrophy in fetuses of diabetic mothers remains controversial. Although fetal hyperinsulinism has long been suggested as the cause [8], the association between hypertrophic cardiomyopathy and high insulin levels in amniotic fluid has only recently been demonstrated [9–12]. In keeping with this, post-natal regression of cardiomyopathy is related to normalization of insulin levels [12]. However, even though macrosomia is a common finding in neonates of diabetic mothers, no association with the development of fetal septal hypertrophy has
Several studies have demonstrated that left ventricular diastolic function is impaired in fetuses with myocardial hypertrophy [14,15]. Classical echocardiographic assessment of fetal diastolic function uses Doppler analysis of mitral and tricuspid inflow signals. Pulsed wave Doppler waveforms obtained in diastole at the tip of both atrioventricular valves are biphasic, with an E-wave representing early ventricular filling velocity, and an A-wave related to flow velocity during atrial contraction, in pre-systole. The normal E/A ratio during pregnancy is below 1, an indication that the fetal myocardium is relatively ‘stiff’ compared to that of newborns and older children. While an increase or inversion of the E/A ratio is related to ventricular diastolic dysfunction [14–16], differences in the pattern of atrioventricular flow in fetuses of diabetic mothers do not necessarily depend only on alterations in ventricular compliance [17]. 4. Alternative and newer methods to assess ventricular diastolic function The fetal circulation has unique characteristic features. Thus, traditional post-natal methods to assess ventricular diastole may not be sufficient to assess cardiac function prenatally. In fetuses of diabetic mothers, the myocardial hypertrophy decreases myocardial distensibility and causes alterations in left atrial dynamics, due to the increased left ventricular end-diastolic pressure. The consequences of the increment in left atrial pressure may be assessed by alternative parameters. 4.1. Mobility of the septum primum The flap valve of the foramen ovale is also called septum primum. This is a left atrial structure that will close the natural interatrial communication after birth. Typically in the fetus, the flap valve bulges toward the left atrial cavity throughout each cardiac cycle. We hypothesized that the magnitude of movement of the septum primum could be related to left atrial pressure and dynamics. To assess this diastolic mobility, we measured its “excursion index” (EI), defined as the ratio between the maximal linear displacement of the flap valve and the left atrial diameter in a four-chamber view [18] (Fig. 2A). We have shown that the EI was lower in third trimester fetuses of diabetic mothers with septal hypertrophy than in fetuses without myocardial hypertrophy and fetuses from a control group of normoglycemic mothers. In addition, a significant inverse correlation between septal hypertrophy and EI of the septum primum was observed. In normal fetuses, no correlation between the mobility of the septum primum and the diameter of the foramen ovale was found [19]. We suggested that the increase in left atrial diastolic pressure as a result of the less compliant hypertrophic left ventricle interferes with the normal mobility of the atrial flap valve, limiting its movement. Similar behavior of the septum primum mobility has been demonstrated in fetuses with intrauterine growth restriction, reflecting diastolic dysfunction [20]. 4.2. Left atrial shortening fraction (LASF)
Fig. 1. A: Cross-sectional four-chamber view from a 33-week fetus of a diabetic mother with severe septal hypertrophy. B: M-mode tracing obtained from the same case showing increased thickness of the interventricular septum (distance between markers = 6.3 mm). RV = right ventricle; LV = left ventricle; IVS = interventricular septum.
To assess LASF, fetal echocardiography was performed in women with pre-existing or gestational diabetes and in non-diabetic controls between 25 weeks gestation and term [21]. In all, LASF was calculated using M-mode measurements according to the formula: (end-systolic
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Fig. 2. A: Four-chamber view obtained from a 28-week fetus. ‘A’ represents maximal excursion of the septum primum; ‘B’ represents maximal diameter of the left atrium. The ratio A/B expresses the excursion index of the septum primum. B: M-mode imaging through the left atrium obtained from a normal fetus at 29 weeks. Markers illustrate measurements for calculation of left atrial shortening fraction, obtained by the ratio (maximal diameter − minimal diameter) / maximal diameter. LA = left atrium, RA = rigtht atrium; RV = right ventricle; LA = left atrium; LV = left ventricle.
diameter − end-diastolic diameter)/ end-systolic diameter (Fig. 2B), and data were compared among the three groups. We have demonstrated that LASF is lower in fetuses with myocardial hypertrophy than in those without hypertrophy. A significant inverse linear correlation between LASF and interventricular septal thickness was also found. This study has shown that diastolic dysfunction also occurs in diabetic fetuses without myocardial hypertrophy as shown by a significantly lower LASF compared to controls [21]. Studies carried out in adults have shown that the dynamics of the left atrial wall is related to left ventricular compliance, especially in patients with hypertrophic cardiomyopathy. Thus, LASF appears to be dependent on left ventricular preload and to be proportional to ventricular compliance [22]. 4.3. Impedance to foramen ovale flow The fetal foramen ovale has anatomical and functional vascular characteristics during the cardiac cycle, showing a triphasic venous flow profile. For this reason, the foramen ovale pulsatility index (PI), calculated by the Doppler ratio: (peak systolic velocity − peak pre-systolic velocity) / mean velocity, may be used as a parameter to assess its vascular impedance. We have shown that fetuses of diabetic mothers with myocardial hypertrophy had significantly higher foramen ovale flow PI than fetuses without hypertrophy, both of diabetic and normal control mothers. This finding was due to a significant reduction in pre-systolic velocity (“more negative” a wave) observed in fetuses with increased myocardial thickness, strengthening the idea that in late diastole, during atrial contraction, the events occurring in the hypertrophic left ventricle decrease its compliance, thus influencing the flow across the foramen ovale [23] (Fig. 3A).
Fig. 3. A: Pulsed wave Doppler across the foramen ovale obtained from the same fetus shown in Fig. 1. There is a prominent pre-systolic wave with an increased pulsatility index (PI = 3.7 normal ≤ 2.5), reflecting diastolic dysfunction. B: Doppler tracing of pulmonary vein flow from a 31-week healthy fetus depicting normal PI (= 0.8, normal ≤ 1.2). The signal was obtained by placing the pulsed Doppler sample volume over the right superior pulmonary vein, as near as possible to its junction with the left atrium. S = systolic peak; D = diastolic peak; A = pre-systolic peak.
4.4. Impedance to pulmonary venous flow Pulmonary venous flow pattern is mainly determined by events that occur in the left side of the heart [24]. It is influenced by dynamic changes in left atrial pressure created by contraction and relaxation of both atrium and ventricle. An increase in its PI is a marker of retrograde transmission of pressure, as this index reflects the relationship between systolic, pre-systolic and mean pulmonary venous flow velocity. We have demonstrated that fetuses of diabetic mothers have a higher PI in the pulmonary veins than fetuses from mothers with normal glycemia [25]. The increase in left atrial pressure leads to a restriction of pulmonary venous emptying, resulting in either a decrease in pre-systolic velocity or reverse flow in pre-systole. The pulmonary vein PI, also related to impedance to forward flow, is independent of the insonation angle and thus, better than absolute measurement values of individual waveform velocities [25,26] (Fig. 3B). In the normal fetus, the pulmonary venous flow pulsatility decreases as the vein is sampled from the lung to the heart, being inversely correlated to the diameter of the pulmonary vein, which increases from its proximal to distal portion [27].
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4.5. Impedance to ductus venosus flow Ductus venosus flow plays a fundamental role in fetal hemodynamics, and its analysis has been the subject of study in several pathological situations. Flow of highly saturated blood through the foramen ovale depends directly on the velocity of ductus venosus flow, its PI reflecting its impedance. We have assessed ductus venosus PI related to myocardial hypertrophy and fetal diastolic ventricular function in maternal diabetes. Fetuses of diabetic mothers with septal hypertrophy showed a significantly higher ductus venosus PI than those of diabetic mothers without septal hypertrophy and control fetuses. No difference was observed in mitral and tricuspid A wave velocities. These results suggest that ventricular compliance is impaired as a consequence of myocardial hypertrophy and maternal diabetes, indicating that the assessment of the ductus venosus may be more sensitive than the analysis of atrioventricular flows for detecting a decrease in ventricular compliance [28] (Fig. 4A). 4.6. Fetal ventricular diastolic function assessed by tissue Doppler Tissue Doppler now represents one of the most recent echocardiographic approaches to study and analyze fetal cardiac diastolic
function. This technique allows direct evaluation of myocardial velocities throughout the cardiac cycle and avoids the limitations imposed by high heart rate and loading conditions associated with Doppler analysis of atrioventricular diastolic flow [29–31]. In fetuses of diabetic mothers, it has been suggested that diastolic dysfunction may precede myocardial hypertrophy. Using tissue Doppler, we have assessed fetal diastolic function in such fetuses, with or without myocardial hypertrophy and compared the findings to those obtained in fetuses of non-diabetic mothers (Fig. 5). In controls, early diastolic velocities (E′) at mitral, tricuspid and septal levels are almost always lower than late tissue velocities (A′). Additionally, right and left ventricular myocardial wall velocities (E′ and A′) are usually higher than septal velocities. Similar differences according to site of myocardial sampling are also observed in fetuses of diabetic mothers. However, when compared to normal fetuses, diastolic myocardial velocities at the level of the aortic and mural leaflets of mitral valve and tricuspid valve annulus, are significantly higher in fetuses of diabetic mothers. Further post-hoc analysis has also shown that these changes in diastolic function do not depend on the presence of fetal ventricular hypertrophy. Furthermore, significantly lower ratios of flow to myocardial velocities (E/E′ ratio) were observed in both atrioventricular valves in fetuses of diabetic mothers compared to controls, as a result of higher myocardial velocities (E′), rather than changes in early atrioventricular diastolic flow velocities (E). In adults with aortic stenosis, mitral E/E′ ratio has been positively correlated with increased left ventricular filling pressure: lower E′ velocities, higher E/E′ ratio [32]. On the other hand, significantly lower mitral valve E/E′ ratio has been found in patients with ischemic disease and more compromised left ventricular function [33]. Thus, in the fetus of a diabetic mother, we can only speculate on the reasons for the higher myocardial velocities at the level of the atrioventricular annuli. Since during atrial filling there is a displacement of the mitral annulus toward the apex and this effect is reversed during early ventricular filling, a less compliant left ventricle could favor a more abrupt return of the mitral annulus to its initial position. Since many of these patients have not shown changes in trans-mitral or trans-tricuspid flow as assessed by pulsed wave Doppler, the above data suggests that tissue Doppler may be more sensitive than conventional Doppler for the diagnosis of fetal diastolic dysfunction. It appears that maternal diabetes mellitus is associated with intrinsic alterations in fetal left ventricular diastolic function and not only as a result of myocardial hypertrophy [34]. 4.7. Fetal aortic isthmus flow index (AIFI) Since the early studies by Fouron and colleagues in 1993 [35–37], much have been investigated about the role of the aortic isthmus flow index on the fetal circulation, obtained by the ratio: (systolic-
Fig. 4. A: Ductus venosus Doppler flow signal from the same healthy 31-week fetus as in Fig. 3B. B: Aortic isthmal flow signal obtained from the same fetus shown in Fig. 1, with severe septal hypertrophy. Due to a decrease in diastolic flow signal, the isthmal flow index is decreased ((IFI=1.05, normal≥1.2). S = systolic flow; D = diastolic flow; = pre-systolic flow.
Fig. 5. Myocardial tissue Doppler signal obtained from a 30 week-fetus of a control non-diabetic mother. The E′/A′ ratio is normal (0.60).
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time integral+ diastolic velocity-time integral) / systolic time integral. According to these early studies, the aortic isthmus is the only true arterial shunt in the fetus, and thus influences the balance between cerebral and placental circulations in many pathological conditions. Since the pattern of isthmal flow includes a systolic antegrade component dependent on both left and right ventricular ejection and a diastolic antegrade component which depends on cerebral and placental resistances, changes in cardiac function may influence the behavior of the aortic isthmus flow. We hypothesized that an increase in right ventricular output in fetuses of diabetic mothers, as a result of increased impedance to flow through the foramen ovale, ductus venosus and pulmonary veins, secondary to a higher left atrial pressure, could interfere with diastolic antegrade flow across the aortic isthmus and lead to a decrease in the AIFI (Fig. 4B). We have observed a lower AIFI in fetuses of diabetic mothers, with or without myocardial hypertrophy, than in fetuses of normal control mothers, in keeping with the proposed hypothesis [38]. 5. Ongoing studies on fetal diastolic function in maternal diabetes Another parameter, namely left ventricular isovolumic relaxation time (IVRT) is the subject of an ongoing study of cardiac function in diabetic pregnancies. A summary is presented below (unpublished observation) We have also constructed a numerical score to quantify fetal global diastolic function using the several parameters discussed herein and suggest that this score may be useful in monitoring such pregnancies (see future research directions).
impedance to pulmonary venous flow, impedance to ductus venosus flow, tissue Doppler and aortic isthmus flow index. 7. Future research directions • Additional Doppler-derived parameters such as ‘left ventricular isovolumetric relaxation time’ may prove useful in the assessment of global fetal diastolic function. • To evaluate means of predicting outcome in fetuses of diabetic mothers based on the degree of functional compromise. A score of left ventricular diastolic dysfunction based on several echocardiographic parameters is proposed (see Appendix A, validation of this score is ongoing). • Although the proposed fetal diastolic dysfunction score has been created to grade fetal and neonatal risk in maternal diabetes, it may also be tested in other clinical settings where left ventricular diastolic function may be impaired, such as intrauterine growth restriction. Conflict of interest statement There are no conflict of interest. Appendix A Proposed scoring system to assess fetal diastolic dysfunction.
5.1. Left ventricular isovolumic relaxation time in the fetus Left ventricular IVRT represents the earliest phase of diastole, corresponding to the time interval between closure of the aortic valve and opening of mitral valve. Changes in left ventricular compliance and relaxation may prolong this time interval [16]. In maternal diabetes, the altered left ventricular diastolic function is expected to increase IVRT. This is in keeping with our observations in a prospective study comparing fetuses of diabetic mothers, with and without hypertrophy, with controls. We have shown that fetuses with myocardial hypertrophy had higher left IVRT intervals than those without. Furthermore, even without increased ventricular mass, fetuses of diabetic mothers had larger IVRT intervals than normal controls. These observations suggest that IVRT might be a sensitive tool to detect fetal diastolic dysfunction in maternal diabetes, even before the appearance of myocardial hypertrophy. 6. Key guidelines • The most frequent prenatal presentation of myocardial hypertrophy is seen in fetuses of diabetic mothers. • Hypertrophic cardiomyopathy in neonates of diabetic mothers is a transient disorder, with spontaneous regression during the first 6 months of postnatal life, related to the normalization of insulin levels. • However benign, this disorder may cause neonatal cardiomegaly and respiratory distress secondary to poor left ventricular compliance. • Cardiac function in fetuses of diabetic mothers may be altered when maternal glycated hemoglobin is increased. • Myocardial hypertrophy in fetuses of diabetic mothers, leading to a decrease in myocardial distensibility, alters left atrial dynamics, due to the increased left ventricular end-diastolic pressure. • The fetal circulation has unique characteristic features. Assessment of ventricular diastolic function based on atrioventricular valves flow analysis alone is insufficient to assess fetal cardiac function. • The consequences of the increment in left atrial pressure may be assessed by alternative parameters: mobility of the septum primum, impedance to foramen ovale flow, left atrial shortening fraction,
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Septum primum EI Left atrium SF Mitral E/A ratio Pulmonary vein PI Ductus venosus PI Foramen ovale PI AIFI Myocardial hypertrophy
3 points
2 points
1 point
0 points
b0.25 b0.25 >1.0 >2.0 >2.0 >3.5 b1.0 Present = 4 Absent = 0
0.26–0.35 0.26–0.35 0.9–1.0 1.5–2.0 1.5–2.0 3.0–3.5 1.0–1.09
0.36–0.45 0.36–0.45 0.8–0.9 1.2–1.4 1.2–1.4 2.5–2.9 1.10–1.20
>0.45 >0.45 b 0.8 b 1.2 b 1.2 b 2.5 > 1.20
Myocardial hypertrophy is considered a categorical variable (absent = 0, present = 1). The other seven parameters are assigned 0, 1, 2 or 3 points. ‘Zero’ points equate to a normal value. One, two or three points are arbitrarily given to different cut-off values, as appropriate for each parameter. Minimal score = 0, maximal score = 25. EI = excursion índex, PI = pulsatility índex, SF = shortening fraction, AIFI = aortic isthmus flow índex. Degree of diastolic dysfunction according to the scoring system Fetal diastolic dysfunction score Zero points 1–10 points 11–20 points > 20 points
Absent Mild Moderate Severe
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[23] Zielinsky P, Manica SJL, Piccoli Jr AL, Nicoloso LH, Scheid M, Frajndlich R, et al. Behavior of the foramen ovale flow in fetuses of diabetic mothers and myocardial hypertrophy. Rev Bras Ecocardiogr 2005;18:15–21. [24] Keren G, Sherez J, Megidish R, Levitt B, Laniado S. Pulmonary venous flow patternits relationship to cardiac dynamics. A pulsed Doppler echocardiographic study. Circulation 1985;71:1105–12. [25] Zielinsky P, Piccoli Jr AL, Teixeira L, Gus E, Mânica JL, Satler F, et al. Pulmonary vein pulsatility in fetuses of diabetic mothers: prenatal Doppler echocardiographic study. Arq Bras Cardiol 2003;81 604–7, 0–3. [26] Lenz F, Chaoui R. Reference ranges for Doppler-assessed pulmonary venous blood flow velocities and pulsatility indices in normal human fetuses. Prenat Diagn 2002;22:786–91. [27] Zielinsky P, Piccoli Jr AL, Gus E, Mânica JL, Satler F, Nicoloso LH, et al. Dynamics of the pulmonary venous flow in the fetus and its association with vascular diameter. Circulation 2003;108:2377–80. [28] Zielinsky P, Marcantonio S, Nicoloso LH, Piccoli Jr AL, Gus E, Mânica JL, et al. Ductus venosus flow and myocardial hypertrophy in fetuses of diabetic mothers. Arq Bras Cardiol 2004;83 51–6; 45–50. [29] Allan LD, Chita SK, Al-Ghazali W, Crawford DC, Tynan M. Doppler echocardiographic evaluation of the normal human fetal heart. Br Heart J 1987;57(6): 528–33. [30] McDicken WN, Sutherland GR, Moran CM, Gordon LN. Colour Doppler velocity imaging of the myocardium. Ultrasound Med Biol 1992;18:651–4. [31] Miyatakea K, Yamagishia M, Tanakaa N, Uematsua M, Yamazakia N, Minea Y, et al. New method for evaluating left ventricular wall motion by color-coded tissue Doppler imaging: in vitro and in vivo studies. J Am Coll Cardiol 1995;25:717–24. [32] Bruch C, Stypmann J, Grude M, Gradaus R, Breithardt G, Wichter T. Tissue Doppler imaging in patients with moderate to severe aortic valve stenosis: clinical usefulness and diagnostic accuracy. Am Heart J 2004;148:696–702. [33] Baykan M, Yilmaz R, Celik S, Orem C, Kaplan S, Erdol C. Assessment of left ventricular systolic and diastolic function by Doppler tissue imaging in patients with preinfarction angina. J Am Soc Echocardiogr 2003;16:1024–30. [34] Hatém MA, Zielinsky P, Hatém DM, Nicoloso LH, Manica JL, Piccoli AL, et al. Assessment of diastolic ventricular function in fetuses of diabetic mothers using tissue Doppler. Cardiol Young 2008;18:297–302. [35] Bonnin P, Fouron JC, Teyssier G, Sonesson SE, Skoll A. Quantitative assessment of circulatory changes in the fetal aortic isthmus during progressive increase of resistance to umbilical blood flow. Circulation 1993;88:216–22. [36] Fouron JC, Siles A, Montanari L, Morin L, Ville Y, Mivelaz Y, et al. Feasibility and reliability of Doppler flow recordings in the fetal aortic isthmus: a multicenter evaluation. Ultrasound Obstet Gynecol 2009;33:690–3. [37] Fouron JC, Zarelli M, Drblik P, Lessard M. Flow velocity profile of the fetal aortic isthmus through normal gestation. Am J Cardiol 1994;74:483–6. [38] Zielinsky P, Frajndlich R, Nicoloso LH, Manica JL, Piccoli Jr AL, Morais M, et al. Aortic isthmus blood flow in fetuses of diabetic mothers. Prenat Diagn 2011;31:1176–80.
Contents lists available at SciVerse ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Best practice guidelines
Myocardial hypertrophy and dysfunction in maternal diabetes Paulo Zielinsky ⁎, Antonio Luiz Piccoli Jr. ⁎⁎ Fetal Cardiology Unit, Institute of Cardiology, Porto Alegre, Brazil
a r t i c l e
i n f o
Keywords: Fetal heart Fetal cardiac function Fetal diastolic dysfunction Diabetes in pregnancy
a b s t r a c t Diabetes in pregnancy, both pre-gestational and gestational, is a frequent cause of fetal myocardial hypertrophy, partly due to fetal hyperinsulinism. In fetal life, cardiac function may be impaired, especially during diastole, as a result of decreased left ventricular distensibility and altered left atrial dynamics secondary to myocardial hypertrophy. In neonates, the hypertrophy is a transient disorder, with spontaneous regression of the increased myocardial thickness during the first months of life. Nevertheless, cardiac hypertrophy may be associated with neonatal cardiomegaly and respiratory distress secondary to poor left ventricular compliance. The development of a number of new echocardiographic parameters discussed in this article, and primarily based on the pathophysiological consequences of myocardial hypertrophy, highlight an area of research priority: the assessment of diastolic function in fetuses of diabetic mothers with (and without) myocardial hypertrophy. A score for grading the severity of fetal diastolic dysfunction in these fetuses is proposed. © 2012 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Myocardial hypertrophy in fetuses of diabetic mothers . . . . . . . . Conventional Doppler assessment of ventricular diastolic function . . . Alternative and newer methods to assess ventricular diastolic function 4.1. Mobility of the septum primum . . . . . . . . . . . . . . . . 4.2. Left atrial shortening fraction (LASF) . . . . . . . . . . . . . 4.3. Impedance to foramen ovale flow . . . . . . . . . . . . . . . 4.4. Impedance to pulmonary venous flow . . . . . . . . . . . . 4.5. Impedance to ductus venosus flow . . . . . . . . . . . . . . 4.6. Fetal ventricular diastolic function assessed by tissue Doppler . 4.7. Fetal aortic isthmus flow index (AIFI) . . . . . . . . . . . . . 5. Ongoing studies on fetal diastolic function in maternal diabetes . . . . 5.1. Left ventricular isovolumic relaxation time in the fetus. . . . . 6. Key guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Future research directions . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Pre-gestational maternal diabetes is a risk factor for fetal structural heart disease. However, fetal cardiac function may be impaired as
⁎ Correspondence to: P. Zielinsky, Av. Cristóvão Colombo 3038 ap. 303, 90560-002 Porto Alegre, RS, Brazil. Tel.: + 55 51 99696227; fax: + 55 51 30619997. ⁎⁎ Correspondence to: A.L. Piccoli Jr, Av. Princesa Isabel 395, 90620-001 Porto Alegre, RS, Brazil. Tel.: + 55 51 98182593; fax: + 55 51 30619997. E-mail addresses: [email protected] (P. Zielinsky), [email protected] (A.L. Piccoli). 0378-3782/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2012.02.006
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a result of myocardial hypertophy, which is prevalent in both gestational and pre-gestational diabetic pregnancies. Post-natally, the increased myocardial thickness (often referred to as ‘diabetic hypertrophic cardiomyopathy’) is transient, with spontaneous regression during the first months of life. Despite this transient nature, neonates of diabetic mothers may present with cardiomegaly and respiratory distress, the latter secondary to poor left ventricular compliance. These findings stress the need for adequate prenatal assessment of diastolic function. In the fetus of diabetic mothers with myocardial hypertrophy, cardiac function may be impaired, especially during diastole, as a
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result of a decreased left ventricular distensibility and altered left atrial dynamics secondary to myocardial hypertrophy. Assessment of diastolic function in these fetuses has become an area of priority for research due to the development of a number of new echocardiographic parameters, which are reviewed in this article.
been found [2]. On the other hand, the increase in septal thickness throughout pregnancy is associated with increased levels of insulin growth factor-1. Fetal cardiac function is also reduced when preconceptual maternal glycated hemoglobin is increased [13]. 3. Conventional Doppler assessment of ventricular diastolic function
2. Myocardial hypertrophy in fetuses of diabetic mothers The most frequent cause of myocardial hypertrophy seen prenatally is observed in fetuses of diabetic mothers. It occurs as a complication of gestational or previous maternal diabetes in about 25–30% of cases [1]. The ventricular septum is preferentially affected, but both right and left ventricular free walls may be involved, predominantly the left [2] (Fig. 1). In-utero manifestation of myocardial hypertrophy is often not striking, but the hypertrophy is easily detected by standard fetal echocardiography, usually by comparing septal thickness with established nomograms [3,4]. Septal thickness greater than two standard deviations for gestational age is considered abnormal. Histological features include increased nuclear and sarcolemmal mass, as well as vacuolization and hydrops of hyperplastic myocardial cells [5–7]. The etiology of myocardial hypertrophy in fetuses of diabetic mothers remains controversial. Although fetal hyperinsulinism has long been suggested as the cause [8], the association between hypertrophic cardiomyopathy and high insulin levels in amniotic fluid has only recently been demonstrated [9–12]. In keeping with this, post-natal regression of cardiomyopathy is related to normalization of insulin levels [12]. However, even though macrosomia is a common finding in neonates of diabetic mothers, no association with the development of fetal septal hypertrophy has
Several studies have demonstrated that left ventricular diastolic function is impaired in fetuses with myocardial hypertrophy [14,15]. Classical echocardiographic assessment of fetal diastolic function uses Doppler analysis of mitral and tricuspid inflow signals. Pulsed wave Doppler waveforms obtained in diastole at the tip of both atrioventricular valves are biphasic, with an E-wave representing early ventricular filling velocity, and an A-wave related to flow velocity during atrial contraction, in pre-systole. The normal E/A ratio during pregnancy is below 1, an indication that the fetal myocardium is relatively ‘stiff’ compared to that of newborns and older children. While an increase or inversion of the E/A ratio is related to ventricular diastolic dysfunction [14–16], differences in the pattern of atrioventricular flow in fetuses of diabetic mothers do not necessarily depend only on alterations in ventricular compliance [17]. 4. Alternative and newer methods to assess ventricular diastolic function The fetal circulation has unique characteristic features. Thus, traditional post-natal methods to assess ventricular diastole may not be sufficient to assess cardiac function prenatally. In fetuses of diabetic mothers, the myocardial hypertrophy decreases myocardial distensibility and causes alterations in left atrial dynamics, due to the increased left ventricular end-diastolic pressure. The consequences of the increment in left atrial pressure may be assessed by alternative parameters. 4.1. Mobility of the septum primum The flap valve of the foramen ovale is also called septum primum. This is a left atrial structure that will close the natural interatrial communication after birth. Typically in the fetus, the flap valve bulges toward the left atrial cavity throughout each cardiac cycle. We hypothesized that the magnitude of movement of the septum primum could be related to left atrial pressure and dynamics. To assess this diastolic mobility, we measured its “excursion index” (EI), defined as the ratio between the maximal linear displacement of the flap valve and the left atrial diameter in a four-chamber view [18] (Fig. 2A). We have shown that the EI was lower in third trimester fetuses of diabetic mothers with septal hypertrophy than in fetuses without myocardial hypertrophy and fetuses from a control group of normoglycemic mothers. In addition, a significant inverse correlation between septal hypertrophy and EI of the septum primum was observed. In normal fetuses, no correlation between the mobility of the septum primum and the diameter of the foramen ovale was found [19]. We suggested that the increase in left atrial diastolic pressure as a result of the less compliant hypertrophic left ventricle interferes with the normal mobility of the atrial flap valve, limiting its movement. Similar behavior of the septum primum mobility has been demonstrated in fetuses with intrauterine growth restriction, reflecting diastolic dysfunction [20]. 4.2. Left atrial shortening fraction (LASF)
Fig. 1. A: Cross-sectional four-chamber view from a 33-week fetus of a diabetic mother with severe septal hypertrophy. B: M-mode tracing obtained from the same case showing increased thickness of the interventricular septum (distance between markers = 6.3 mm). RV = right ventricle; LV = left ventricle; IVS = interventricular septum.
To assess LASF, fetal echocardiography was performed in women with pre-existing or gestational diabetes and in non-diabetic controls between 25 weeks gestation and term [21]. In all, LASF was calculated using M-mode measurements according to the formula: (end-systolic
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Fig. 2. A: Four-chamber view obtained from a 28-week fetus. ‘A’ represents maximal excursion of the septum primum; ‘B’ represents maximal diameter of the left atrium. The ratio A/B expresses the excursion index of the septum primum. B: M-mode imaging through the left atrium obtained from a normal fetus at 29 weeks. Markers illustrate measurements for calculation of left atrial shortening fraction, obtained by the ratio (maximal diameter − minimal diameter) / maximal diameter. LA = left atrium, RA = rigtht atrium; RV = right ventricle; LA = left atrium; LV = left ventricle.
diameter − end-diastolic diameter)/ end-systolic diameter (Fig. 2B), and data were compared among the three groups. We have demonstrated that LASF is lower in fetuses with myocardial hypertrophy than in those without hypertrophy. A significant inverse linear correlation between LASF and interventricular septal thickness was also found. This study has shown that diastolic dysfunction also occurs in diabetic fetuses without myocardial hypertrophy as shown by a significantly lower LASF compared to controls [21]. Studies carried out in adults have shown that the dynamics of the left atrial wall is related to left ventricular compliance, especially in patients with hypertrophic cardiomyopathy. Thus, LASF appears to be dependent on left ventricular preload and to be proportional to ventricular compliance [22]. 4.3. Impedance to foramen ovale flow The fetal foramen ovale has anatomical and functional vascular characteristics during the cardiac cycle, showing a triphasic venous flow profile. For this reason, the foramen ovale pulsatility index (PI), calculated by the Doppler ratio: (peak systolic velocity − peak pre-systolic velocity) / mean velocity, may be used as a parameter to assess its vascular impedance. We have shown that fetuses of diabetic mothers with myocardial hypertrophy had significantly higher foramen ovale flow PI than fetuses without hypertrophy, both of diabetic and normal control mothers. This finding was due to a significant reduction in pre-systolic velocity (“more negative” a wave) observed in fetuses with increased myocardial thickness, strengthening the idea that in late diastole, during atrial contraction, the events occurring in the hypertrophic left ventricle decrease its compliance, thus influencing the flow across the foramen ovale [23] (Fig. 3A).
Fig. 3. A: Pulsed wave Doppler across the foramen ovale obtained from the same fetus shown in Fig. 1. There is a prominent pre-systolic wave with an increased pulsatility index (PI = 3.7 normal ≤ 2.5), reflecting diastolic dysfunction. B: Doppler tracing of pulmonary vein flow from a 31-week healthy fetus depicting normal PI (= 0.8, normal ≤ 1.2). The signal was obtained by placing the pulsed Doppler sample volume over the right superior pulmonary vein, as near as possible to its junction with the left atrium. S = systolic peak; D = diastolic peak; A = pre-systolic peak.
4.4. Impedance to pulmonary venous flow Pulmonary venous flow pattern is mainly determined by events that occur in the left side of the heart [24]. It is influenced by dynamic changes in left atrial pressure created by contraction and relaxation of both atrium and ventricle. An increase in its PI is a marker of retrograde transmission of pressure, as this index reflects the relationship between systolic, pre-systolic and mean pulmonary venous flow velocity. We have demonstrated that fetuses of diabetic mothers have a higher PI in the pulmonary veins than fetuses from mothers with normal glycemia [25]. The increase in left atrial pressure leads to a restriction of pulmonary venous emptying, resulting in either a decrease in pre-systolic velocity or reverse flow in pre-systole. The pulmonary vein PI, also related to impedance to forward flow, is independent of the insonation angle and thus, better than absolute measurement values of individual waveform velocities [25,26] (Fig. 3B). In the normal fetus, the pulmonary venous flow pulsatility decreases as the vein is sampled from the lung to the heart, being inversely correlated to the diameter of the pulmonary vein, which increases from its proximal to distal portion [27].
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4.5. Impedance to ductus venosus flow Ductus venosus flow plays a fundamental role in fetal hemodynamics, and its analysis has been the subject of study in several pathological situations. Flow of highly saturated blood through the foramen ovale depends directly on the velocity of ductus venosus flow, its PI reflecting its impedance. We have assessed ductus venosus PI related to myocardial hypertrophy and fetal diastolic ventricular function in maternal diabetes. Fetuses of diabetic mothers with septal hypertrophy showed a significantly higher ductus venosus PI than those of diabetic mothers without septal hypertrophy and control fetuses. No difference was observed in mitral and tricuspid A wave velocities. These results suggest that ventricular compliance is impaired as a consequence of myocardial hypertrophy and maternal diabetes, indicating that the assessment of the ductus venosus may be more sensitive than the analysis of atrioventricular flows for detecting a decrease in ventricular compliance [28] (Fig. 4A). 4.6. Fetal ventricular diastolic function assessed by tissue Doppler Tissue Doppler now represents one of the most recent echocardiographic approaches to study and analyze fetal cardiac diastolic
function. This technique allows direct evaluation of myocardial velocities throughout the cardiac cycle and avoids the limitations imposed by high heart rate and loading conditions associated with Doppler analysis of atrioventricular diastolic flow [29–31]. In fetuses of diabetic mothers, it has been suggested that diastolic dysfunction may precede myocardial hypertrophy. Using tissue Doppler, we have assessed fetal diastolic function in such fetuses, with or without myocardial hypertrophy and compared the findings to those obtained in fetuses of non-diabetic mothers (Fig. 5). In controls, early diastolic velocities (E′) at mitral, tricuspid and septal levels are almost always lower than late tissue velocities (A′). Additionally, right and left ventricular myocardial wall velocities (E′ and A′) are usually higher than septal velocities. Similar differences according to site of myocardial sampling are also observed in fetuses of diabetic mothers. However, when compared to normal fetuses, diastolic myocardial velocities at the level of the aortic and mural leaflets of mitral valve and tricuspid valve annulus, are significantly higher in fetuses of diabetic mothers. Further post-hoc analysis has also shown that these changes in diastolic function do not depend on the presence of fetal ventricular hypertrophy. Furthermore, significantly lower ratios of flow to myocardial velocities (E/E′ ratio) were observed in both atrioventricular valves in fetuses of diabetic mothers compared to controls, as a result of higher myocardial velocities (E′), rather than changes in early atrioventricular diastolic flow velocities (E). In adults with aortic stenosis, mitral E/E′ ratio has been positively correlated with increased left ventricular filling pressure: lower E′ velocities, higher E/E′ ratio [32]. On the other hand, significantly lower mitral valve E/E′ ratio has been found in patients with ischemic disease and more compromised left ventricular function [33]. Thus, in the fetus of a diabetic mother, we can only speculate on the reasons for the higher myocardial velocities at the level of the atrioventricular annuli. Since during atrial filling there is a displacement of the mitral annulus toward the apex and this effect is reversed during early ventricular filling, a less compliant left ventricle could favor a more abrupt return of the mitral annulus to its initial position. Since many of these patients have not shown changes in trans-mitral or trans-tricuspid flow as assessed by pulsed wave Doppler, the above data suggests that tissue Doppler may be more sensitive than conventional Doppler for the diagnosis of fetal diastolic dysfunction. It appears that maternal diabetes mellitus is associated with intrinsic alterations in fetal left ventricular diastolic function and not only as a result of myocardial hypertrophy [34]. 4.7. Fetal aortic isthmus flow index (AIFI) Since the early studies by Fouron and colleagues in 1993 [35–37], much have been investigated about the role of the aortic isthmus flow index on the fetal circulation, obtained by the ratio: (systolic-
Fig. 4. A: Ductus venosus Doppler flow signal from the same healthy 31-week fetus as in Fig. 3B. B: Aortic isthmal flow signal obtained from the same fetus shown in Fig. 1, with severe septal hypertrophy. Due to a decrease in diastolic flow signal, the isthmal flow index is decreased ((IFI=1.05, normal≥1.2). S = systolic flow; D = diastolic flow; = pre-systolic flow.
Fig. 5. Myocardial tissue Doppler signal obtained from a 30 week-fetus of a control non-diabetic mother. The E′/A′ ratio is normal (0.60).
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time integral+ diastolic velocity-time integral) / systolic time integral. According to these early studies, the aortic isthmus is the only true arterial shunt in the fetus, and thus influences the balance between cerebral and placental circulations in many pathological conditions. Since the pattern of isthmal flow includes a systolic antegrade component dependent on both left and right ventricular ejection and a diastolic antegrade component which depends on cerebral and placental resistances, changes in cardiac function may influence the behavior of the aortic isthmus flow. We hypothesized that an increase in right ventricular output in fetuses of diabetic mothers, as a result of increased impedance to flow through the foramen ovale, ductus venosus and pulmonary veins, secondary to a higher left atrial pressure, could interfere with diastolic antegrade flow across the aortic isthmus and lead to a decrease in the AIFI (Fig. 4B). We have observed a lower AIFI in fetuses of diabetic mothers, with or without myocardial hypertrophy, than in fetuses of normal control mothers, in keeping with the proposed hypothesis [38]. 5. Ongoing studies on fetal diastolic function in maternal diabetes Another parameter, namely left ventricular isovolumic relaxation time (IVRT) is the subject of an ongoing study of cardiac function in diabetic pregnancies. A summary is presented below (unpublished observation) We have also constructed a numerical score to quantify fetal global diastolic function using the several parameters discussed herein and suggest that this score may be useful in monitoring such pregnancies (see future research directions).
impedance to pulmonary venous flow, impedance to ductus venosus flow, tissue Doppler and aortic isthmus flow index. 7. Future research directions • Additional Doppler-derived parameters such as ‘left ventricular isovolumetric relaxation time’ may prove useful in the assessment of global fetal diastolic function. • To evaluate means of predicting outcome in fetuses of diabetic mothers based on the degree of functional compromise. A score of left ventricular diastolic dysfunction based on several echocardiographic parameters is proposed (see Appendix A, validation of this score is ongoing). • Although the proposed fetal diastolic dysfunction score has been created to grade fetal and neonatal risk in maternal diabetes, it may also be tested in other clinical settings where left ventricular diastolic function may be impaired, such as intrauterine growth restriction. Conflict of interest statement There are no conflict of interest. Appendix A Proposed scoring system to assess fetal diastolic dysfunction.
5.1. Left ventricular isovolumic relaxation time in the fetus Left ventricular IVRT represents the earliest phase of diastole, corresponding to the time interval between closure of the aortic valve and opening of mitral valve. Changes in left ventricular compliance and relaxation may prolong this time interval [16]. In maternal diabetes, the altered left ventricular diastolic function is expected to increase IVRT. This is in keeping with our observations in a prospective study comparing fetuses of diabetic mothers, with and without hypertrophy, with controls. We have shown that fetuses with myocardial hypertrophy had higher left IVRT intervals than those without. Furthermore, even without increased ventricular mass, fetuses of diabetic mothers had larger IVRT intervals than normal controls. These observations suggest that IVRT might be a sensitive tool to detect fetal diastolic dysfunction in maternal diabetes, even before the appearance of myocardial hypertrophy. 6. Key guidelines • The most frequent prenatal presentation of myocardial hypertrophy is seen in fetuses of diabetic mothers. • Hypertrophic cardiomyopathy in neonates of diabetic mothers is a transient disorder, with spontaneous regression during the first 6 months of postnatal life, related to the normalization of insulin levels. • However benign, this disorder may cause neonatal cardiomegaly and respiratory distress secondary to poor left ventricular compliance. • Cardiac function in fetuses of diabetic mothers may be altered when maternal glycated hemoglobin is increased. • Myocardial hypertrophy in fetuses of diabetic mothers, leading to a decrease in myocardial distensibility, alters left atrial dynamics, due to the increased left ventricular end-diastolic pressure. • The fetal circulation has unique characteristic features. Assessment of ventricular diastolic function based on atrioventricular valves flow analysis alone is insufficient to assess fetal cardiac function. • The consequences of the increment in left atrial pressure may be assessed by alternative parameters: mobility of the septum primum, impedance to foramen ovale flow, left atrial shortening fraction,
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Septum primum EI Left atrium SF Mitral E/A ratio Pulmonary vein PI Ductus venosus PI Foramen ovale PI AIFI Myocardial hypertrophy
3 points
2 points
1 point
0 points
b0.25 b0.25 >1.0 >2.0 >2.0 >3.5 b1.0 Present = 4 Absent = 0
0.26–0.35 0.26–0.35 0.9–1.0 1.5–2.0 1.5–2.0 3.0–3.5 1.0–1.09
0.36–0.45 0.36–0.45 0.8–0.9 1.2–1.4 1.2–1.4 2.5–2.9 1.10–1.20
>0.45 >0.45 b 0.8 b 1.2 b 1.2 b 2.5 > 1.20
Myocardial hypertrophy is considered a categorical variable (absent = 0, present = 1). The other seven parameters are assigned 0, 1, 2 or 3 points. ‘Zero’ points equate to a normal value. One, two or three points are arbitrarily given to different cut-off values, as appropriate for each parameter. Minimal score = 0, maximal score = 25. EI = excursion índex, PI = pulsatility índex, SF = shortening fraction, AIFI = aortic isthmus flow índex. Degree of diastolic dysfunction according to the scoring system Fetal diastolic dysfunction score Zero points 1–10 points 11–20 points > 20 points
Absent Mild Moderate Severe
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