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Pregnancy-associated cardiac dysfunction and the regulatory role of microRNAs


Many crucial cardiovascular adaptations occur in the body during pregnancy to ensure successful gestation. Maladaptation of the cardiovascular system during pregnancy can lead to complications that promote cardiac dysfunction and may lead to heart failure (HF). About 12% of pregnancy-related deaths in the USA have been attributed to HF and the detrimental effects of cardiovascular complications on the heart can be long-lasting, pre-disposing the mother to HF later in life. Indeed, cardiovascular complications such as gestational diabetes mellitus, preeclampsia, gestational hypertension, and peripartum cardiomyopathy have been shown to induce cardiac metabolic dysfunction, oxidative stress, fibrosis, apoptosis, and diastolic and systolic dysfunction in the hearts of pregnant women, all of which are hallmarks of HF. The exact etiology and cardiac pathophysiology of pregnancy-related complications is not yet fully deciphered. Furthermore, diagnosis of cardiac dysfunction in pregnancy is often made only after clinical symptoms are already present, thus necessitating the need for novel diagnostic and prognostic biomarkers. Mounting data demonstrates an altered expression of maternal circulating miRNAs during pregnancy affected by cardiovascular complications. Throughout the past decade, miRNAs have become of growing interest as modulators and biomarkers of pathophysiology, diagnosis, and prognosis in cardiac dysfunction. While the association between pregnancy-related cardiovascular complications and cardiac dysfunction or HF is becoming increasingly evident, the roles of miRNA-mediated regulation herein remain poorly understood. Therefore, this review will summarize current reports on pregnancy-related cardiovascular complications that may lead to cardiac dysfunction and HF during and after pregnancy in previously healthy women, with a focus on the pathophysiological role of miRNAs.


During pregnancy, various crucial adaptations in the cardiovascular system occur which are necessary for the progression of successful gestation [1]. Maladaptation of the cardiovascular system during pregnancy in previously healthy women can lead to complications that may cause maternal and fetal mortality [2, 3]. Cardiovascular complications during pregnancy may put the mother at risk to develop cardiac dysfunction and subsequent heart failure (HF) [2, 4]. These complications include metabolic changes such as gestational diabetes mellitus (GDM), hypertensive disorders such as preeclampsia (PE) and gestational hypertension (GH), and cardiac structural changes such as peripartum cardiomyopathy (PPCM) [5,6,7,8]. Cardiac complications in pregnancy are becoming increasingly common [9]. In the USA, about 12% of pregnancy-related deaths have been attributed to cardiac dysfunction, and having cardiac dysfunction during pregnancy has been associated with a 7.7-fold increase in the risk of death [9, 10]. Furthermore, the adverse effects of cardiovascular complications on the heart can be long-lasting, pre-disposing the mother to HF later in life [11, 12].

The heart undergoes several structural, metabolic, and functional changes during pregnancy to accommodate the enhanced cardiac output necessary for meeting maternal and fetal demands [13]. These changes are distinct from adverse cardiac remodeling which precedes HF [14]. However, GDM, PE, GH, and PPCM have all been shown to induce cardiac metabolic dysfunction, oxidative stress, fibrosis, apoptosis, and diastolic and systolic dysfunction in the hearts of pregnant women, all of which are hallmarks of HF [14]. The underlying molecular cardiac pathophysiology of these complications is not yet fully elucidated and warrants further investigation. Furthermore, diagnosis of cardiac dysfunction and HF in pregnancy is often made only after clinical symptoms are already present, thus necessitating the need for novel diagnostic and prognostic biomarkers.

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level by binding to the 3’ untranslated region (3′ UTR) of the target mRNA, marking it for early degradation or blocking its translation [15]. MiRNAs are highly conserved between different species and may control multiple signaling pathways at once [16]. Mounting data demonstrates altered circulating miRNA expression in pregnancy affected by cardiovascular complications [17, 18]. Throughout the past two decades, circulating and tissue-specific miRNAs have become of growing interest as modulators and biomarkers of pathophysiology, diagnosis, and prognosis in a variety of cardiovascular disorders including HF [19, 20]. Although a significant number of studies have been published on the association between GDM, PE, GH, PPCM, and cardiac dysfunction or HF, miRNA-mediated regulation herein remains poorly understood.

This review will discuss current reports on pregnancy-related cardiovascular complications that may lead to cardiac dysfunction and HF during and after pregnancy in previously healthy women, with a focus on the pathophysiological role of miRNAs.

Physiological cardiovascular changes during pregnancy

Hemodynamics of the maternal cardiovascular system during pregnancy

The maternal cardiovascular system undergoes several changes during pregnancy. Blood flow increases to meet the metabolic needs of the maternal organs and fetus [13]. Blood volume increases approximately 45% above pre-pregnancy levels [1]. Stroke volume, heart rate, and end-diastolic volume all increase, resulting in enhanced cardiac output [1]. Indeed, cardiac output rises up to 50% above pre-pregnancy levels at about 16–20 weeks of gestation [21]. Both systolic and diastolic arterial blood pressure decrease in the first and second trimesters [21, 22]. However, arterial blood pressure rises in the third trimester, returning to baseline by the end of pregnancy [22]. To meet these hemodynamic changes during pregnancy, the heart undergoes structural and functional changes.

Structural and metabolic changes in the heart during pregnancy

Natural volume overload, mechanical stretch, and hormonal changes during pregnancy induce physiological cardiac hypertrophy [23,24,25]. In contrast to pathological cardiac hypertrophy, pregnancy-induced physiological cardiac hypertrophy is characterized by proportional increases in cardiomyocyte size and therefore growth in left ventricular (LV) wall thickness and chamber dimensions [24]. Importantly, myocardial capillary density remains normal. Furthermore, pregnancy-induced physiological hypertrophy is not associated with fibrosis, cardiomyocyte sarcomere disarray, or enhanced re-expression of the cardiac fetal gene program [24]. Notably, the changes in cardiac structure and function during normal healthy pregnancy are rapidly reversed post-partum [26].

Metabolic changes in the heart during pregnancy are in contrast to those in pathological cardiac hypertrophy and HF. HF is characterized by a switch from myocardial fatty acid oxidation as a main source of energy to enhanced utilization of glucose [27]. Animal models in various studies have demonstrated that pregnancy is associated with a decrease in cardiac glucose utilization and increased utilization of fatty acids [28,29,30]. However, a decrease in cardiac fatty acid oxidation genes has also been reported [31]. Interestingly, cardiac insulin signaling and mitochondrial function remain unaltered in pregnancy-induced hypertrophy in mice, while they are depressed in pathological cardiac hypertrophy and HF [28, 32, 33].

Signaling pathways regulating the cardiac phenotype during pregnancy

Cardiac molecular signaling pathways activated in pregnancy-induced hypertrophy are distinct from those activated during pathological hypertrophy [23]. Some of these pathways have been demonstrated to be regulated by miRNAs. The best characterized miRNA-regulated pathways in pregnancy-induced cardiac hypertrophy include phosphoinositide-3-kinase/protein kinase B/glycogen synthase kinase 3β (PI3K/Akt/ GSK3β) signaling, mitogen-activated protein kinase (MAPK) signaling, calcineurin signaling, and signal transducer and activator of transcription 3 (STAT3) signaling [34, 35].

Phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase 3 beta (GSK3β)

The PI3K/Akt pathway has been demonstrated as an important mediator in pregnancy-induced cardiac hypertrophy in several studies. The major target of PI3K/Akt signaling is GSK3β, an inhibitor of pathological cardiac hypertrophic signaling that becomes inactivated by Akt-mediated phosphorylation [36]. A large number of studies suggest that PI3K/Akt/GSK3β signaling is cardio-protective and mediates physiological rather than pathological cardiac hypertrophy. All three components of the signaling cascade have been shown to be of great importance for cardio-protection. Indeed, mice with cardiomyocyte-specific expression of constitutively active forms of PI3K and Akt respectively have been shown to develop cardiac hypertrophy with preserved contractility and systolic function, without cell death or fibrosis [37,38,39,40,41]. Furthermore, male mice with cardiomyocyte-specific expression of dominant-negative forms of PI3K and Akt respectively have a diminished physiological hypertrophic response, but enhanced hypertrophy and cardiac dysfunction in response to pressure overload by transverse aortic constriction (TAC) [38, 39]. Akt activation, as measured by phosphorylation status, is upregulated in the LV of pregnant mice and rats, during mid- and late pregnancy [34, 42]. In contrast, one study has also reported the downregulation of phosphorylated Akt in the hearts of pregnant rats compared to non-pregnant rats, which is restored postpartum [43]. This discrepancy could be explained by differences in the estrus cycle of non-pregnant control animals since estrogen levels vary during the estrus cycle in non-pregnant mice [44]. Estrogen is also known to activate MAPK and PI3K/Akt pathways [45, 46]. We have shown previously that estrogen increases tyrosine kinase c-Src activity (phosphorylation) in the heart mimicking increased c-SRC activity in the late pregnant heart [47]. In addition to GSK3β, other targets of PI3K/Akt signaling, such as the mammalian target of rapamycin (mTOR) and ribosomal S6 protein kinase (p706SK) have also been demonstrated to be upregulated in mouse hearts in mid-pregnancy [34]. Interestingly, compared to wild type (WT), mice expressing constitutively-active Akt had larger hearts when non-pregnant which did not undergo further hypertrophy [34]. Along the same lines, mice expressing constitutively active, inhibiting, GSK3β were blocked in their hypertrophic response to pregnancy [34]. Taken together, both Akt and GSK3β are important mediators of pregnancy-induced cardiac hypertrophy [34].

Mitogen-activated protein kinases (MAPKs)

During pregnancy, hormonal changes and mechanical stretch of cardiomyocytes alter the activation of several MAPK signaling pathways [34, 48]. MAPKs mediate various cellular responses in the healthy and diseased heart including hypertrophy, apoptosis, proliferation, differentiation, survival, and inflammatory responses [49]. In the heart, extracellular signal-regulated kinase (ERK) is protective against adverse remodeling, while p38 MAPK and c-Jun N-terminal kinase (JNK) are associated with stress responses [24, 34, 49]. Additionally, crosstalk between ERK and p38 and JNK MAPKs regulates various processes in the heart [49]. Various transgenic mouse models illustrate the importance of MAPK in physiological cardiac hypertrophy. Mice expressing cardiac-specific constitutively active MAPK kinase 1 (MEK1), a direct upstream activator of ERK1/2, but that does not activate JNK and p38, exhibit cardiac hypertrophy with enhanced cardiac function without decompensation over time, reminiscent of physiological cardiac hypertrophy [50]. However, mice lacking the p38 upstream regulator apoptosis signal-regulating kinase 1 were shown to exhibit less adverse cardiac remodeling upon pressure overload by TAC, but more pronounced physiological hypertrophy compared to WT mice [51]. ERK phosphorylation, and thus activation, is shown to be increased in LV of early pregnant rats and mid-pregnant mice [29, 34, 42]. In contrast, phosphorylation of JNK and p38 MAPK are decreased in the hearts of pregnant rats and mice [34, 43]. Furthermore, in pregnant rats, cardiac p-p38 and p-JNK levels were shown to be negatively associated with lower LV mass/volume ratio [43].


Calcium-dependent phosphatase calcineurin is well-known to be upregulated in human hypertrophic and failing hearts and acts as a mediator of adverse cardiac remodeling by mediating nuclear translocation of the pro-hypertrophic transcription factor nuclear factor of activated T-cells (NFAT) [52, 53]. Elevated cardiac calcineurin expression and activity have been demonstrated in early pregnancy, which is partially induced by hormonal changes [54]. Blocking calcineurin using cyclosporine A diminishes the development of pregnancy-induced physiological cardiac hypertrophy in mice [54]. Interestingly, calcineurin inhibition also blocks pregnancy-induced cardiac ERK1/2 and activation [54]. While calcineurin levels remain elevated in pathological hypertrophy and HF, by late pregnancy cardiac calcineurin levels decrease dramatically [31, 54].

Signal transducer and activator of transcription 3 (STAT3)

STAT3 is an important cardio-protective signaling molecule and the transcription factor involved in the pathophysiology of various cardiac diseases [55, 56]. As a transcription factor, STAT3 activates several anti-apoptotic, anti-oxidative, and pro-angiogenic genes in the heart [55]. Interestingly, STAT3 has been shown to both activate and inhibit fibrotic and inflammatory genes in the heart, most likely due to differences in post-translational modifications, and cellular localization [55, 57,58,59,60]. Furthermore, STAT3 has been shown to alter miRNA expression in both the male and female hearts [61, 62]. The non-genomic actions of STAT3 include, among others, a protective function in mitochondria by regulating reactive oxygen species (ROS) production [56, 63]. In mouse heart during pregnancy and postpartum, STAT3 activation, as determined by phosphorylation status, has been shown to be protective in a number of pregnancy-related cardiac insults [64,65,66,67].

Cardiac pathophysiology of cardiovascular complications during pregnancy

Cardiovascular complications reflect an inability to adapt to the various changes in systemic physiology that are associated with pregnancy [3]. While cardiovascular complications in pregnancy may affect multiple organ systems including the liver, kidneys, and brains [68, 69], we focus on the adverse effects on the heart. Indeed, metabolic changes in GDM, elevated blood pressure, and vascular resistance in PE and GH, and LV structural and functional changes in PPCM may all negatively affect cardiac function and may promote HF development [5,6,7,8].

Gestational diabetes mellitus (GDM)

Maintaining glucose homeostasis is of utmost importance during pregnancy for maternal and fetal health as it ensures sufficient glucose levels to promote fetal development while simultaneously maintaining maternal nutrition [69]. GDM is characterized by de novo hyperglycemia occurring in the second or third trimester despite having no previous history of diabetes mellitus [69]. The prevalence of GDM is increasing in parallel with the rise of maternal age and obesity, and is reported to affect approximately 5–14% of pregnancies in the USA [70].

Impaired glucose homeostasis is common in patients with HF even in the absence of hyperglycemia and is likely to contribute to disease progression [71]. As such, GDM was found to be independently associated with greater LV mass, impaired LV relaxation, and LV systolic function [5]. However, GDM patients have also been shown to display only LV diastolic filling impairment without changes in LV mass or systolic function [72]. Strikingly, a history of GDM is associated with a ~ 2-fold increased risk of developing HF up to 25 years postpartum [73,74,75].

Several factors contribute to the pathophysiology of GDM, including insulin resistance, pancreatic β-cell dysfunction, and elevated hepatic gluconeogenesis. Insulin resistance results in impaired plasma membrane translocation of glucose transporter 4 (GLUT4), the primary transporter that is responsible for shuttling glucose into the cell as an energy source [76]. While insulin resistance decreases during normal pregnancy, insulin-stimulated glucose uptake is reported to drop by an extra 54% in GDM patients compared with normal pregnant controls, leading to hyperglycemia [76, 77]. It is important to note that there is a strong association between body weight and insulin resistance in pregnancy [78]. Women weighing more than 95 kg between 24 and 32 weeks of gestation were reported to have significantly higher levels of severe insulin resistance and in turn, a higher risk of GDM [78]. Indeed, in GDM patients, downstream regulators of insulin, including PI3K and GLUT4, have all been shown to be alternatively expressed or activated compared to healthy controls [77]. An increase in serine phosphorylation of insulin receptor substrate has been demonstrated in weeks 30 through 34 of gestation. This leads to a decrease in insulin receptor substrate association with insulin receptor and can inhibit PI3K activity, which in turn, inhibits insulin signaling from activating GLUT4 translocation [79]. Adaptation of insulin-producing pancreatic β cells is critical for a proper response to pregnancy-related insulin resistance and includes increased β cell number, size, and insulin secretion [80]. The adaptation of β cells is thought to be mediated by maternal and placental hormones including prolactin [80]. Prolactin signals through the Akt/mTOR pathway to reduce β cell apoptosis and enhance glucose-stimulated insulin secretion, and through the ERK/MAPK pathway to enhance β cell proliferation [80]. In late gestation, where insulin resistance is at its peak, the maternal system shifts towards a pro-inflammatory immune state [81], which can have adverse outcomes as β cells can be susceptible to macrophage infiltration [82]. However, the mechanism responsible for the inability of β cells to compensate in GDM is yet unknown [80]. During pregnancy, hepatic gluconeogenesis rates increase in healthy women and GDM patients [83, 84]. Together with impaired insulin secretion and sensitivity, higher levels of hepatic gluconeogenesis result in the hyperglycemia observed in GDM patients [69].

Limited research has been conducted on the molecular cardiac pathophysiology of GDM. Recently, GDM was induced in pregnant mice by intraperitoneal injection of streptozotocin (STZ) [85]. Here, retinoic acid treatment attenuated STZ-induced cardiac hypertrophy and fibrosis by enhancing expression of mitochondrial superoxide dismutase (mnSOD), decreasing oxidative stress and reactive oxygen species (ROS) levels, and dampening NF-κB signaling [85]. Changes in LV structure and function reported in GDM are similar to those in diabetic cardiomyopathy [86]. As such, it is tempting to hypothesize that GDM cardiac pathophysiology includes dysregulated insulin/PI3k/Akt/mTOR-mediated autophagy, MAPK-mediated inflammation, mitochondrial dysfunction, apoptosis, and cardiac microvascular dysfunction as is observed in diabetic cardiomyopathy [86].

Preeclampsia (PE) and gestational hypertension (GH)

In the USA, up to 10% of all pregnancies are complicated by hypertensive disorders [87]. Ranging in severity, hypertensive pregnancy disorders can be classified as preeclampsia-eclampsia, gestational hypertension, pre-existing chronic hypertension, and PE superimposed on pre-existing chronic hypertension [88]. Here, we will focus on de novo-developed PE and GH.

Preeclampsia (PE)

PE complicates 5 to 7% of pregnancies and remains the main cause of maternal and fetal morbidity and mortality [89]. Up to now, the only definitive treatment for PE is delivery of the fetus and placenta; however, in some cases, PE can persist or develop postpartum [68]. Currently, PE is diagnosed based on de novo hypertension after 20 weeks of gestation with a systolic BP of ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg, and in severe cases ≥ 160 mm /≥ 110 mm Hg [68]. Furthermore, at least one other symptom indicating maternal organ dysfunction including kidney, liver, neurological and hematological complications, will be present [68, 87].

Elevated systemic vascular resistance in PE may adversely affect cardiac structure and function and as such, PE is associated with both short- and long-term cardiovascular events, including adverse cardiac remodeling and HF [6]. In various stages of disease progression, PE patients have been reported to exhibit decreased cardiac output, higher LV afterload, increased LV mass and LV wall thickness and LV diastolic dysfunction [90,91,92,93,94,95,96,97,98]. Strikingly, women with previous early-onset of preeclampsia have significantly higher fasting blood glucose, insulin, triglycerides, and total cholesterol levels as compared to women with late-onset preeclampsia at the time of follow-up even 3 months postpartum [99]. The increase in these risk factors indicates a higher risk of future CVD in women with previous early-onset preeclampsia [99]. These results highlight the significance of early prevention for patients with preeclampsia.

The exact etiology of PE is still controversial, but placental ischemia seems to play a central role in its onset [68]. The later phase in PE pathophysiology is characterized by elevated circulating levels of the anti-angiogenic factors, a pro-inflammatory state and alterations in the renin-angiotensin pathway and sympathetic nervous system (SNS) [68]. The anti-angiogenic soluble fms-like tyrosine kinase-1 (sFLT1) exerts its effects by binding to the pro-angiogenic protein vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), thus inhibiting their biological activity and causing systemic endothelial dysfunction [100, 101]. Soluble endoglin (sENG) is a transforming growth factor-β1 (TGF-β1) inhibitor and may potentiate sFLT1 vascular effects [102]. Reduced levels of anti-inflammatory cytokine IL-10 and elevated complement system signaling in PE patients contribute to a pro-inflammatory state in PE [103, 104]. Enhanced sensitivity to angiotensin II has been reported in PE patients, despite reduced circulating renin and angiotensin II levels [105]. Furthermore, PE patients are reported to exhibit elevated sympathetic nerve activity [106]. Together, these changes lead to a high systemic vascular resistance state and hypertension in the mother [68, 107].

Novel players have recently emerged in the cardiac pathophysiology of PE. Mutations in the atrial natriuretic peptide-converting enzyme, also known as corin, and transcription factor storkhead box 1 (STOX1) have been shown to associate with PE [108, 109]. Recent studies using transgenic mouse models of corin and STOX1 have demonstrated their role in PE-induced cardiac pathology [110, 111]. Corin-deficient mice or mice expressing mutated corin developed cardiac hypertrophy during pregnancy which persisted postpartum [110]. Pregnant mice with feto-placental STOX1 overexpression developed cardiac hypertrophy with enhanced fibrosis, together with the upregulation of genes involved in renin-angiotensin signaling [111].

Gestational hypertension (GH)

GH is a form of hypertension that appears de novo after 20 weeks of gestation, but in contrast to PE, does not involve dysfunction of other organ systems [87]. GH affects 6 to 7% of pregnancies and is diagnosed as systolic BP of ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg without proteinuria [87, 89]. While GH is a risk factor for PE, it is important to note that GH and PE are separate disorders. It is yet unclear whether GH etiology is distinct from PE. However, the inflammatory response signature is shown to be different between patients with GH and PE [112].

Cardiac LV structure and function in GH patients is altered compared to normotensive pregnant women. Patients suffering from GH have been reported to exhibit reduced ejection fraction (EF), alterations in end-systolic volume, increased LV mass and wall thickness, and LV diastolic dysfunction in varying degrees [7, 95, 113,114,115,116,117]. However, cardiac impairments in GH patients are not as large as in PE patients, likely because PE is not encompassed by hypertension alone, but rather a multi-organ system disorder [7]. Like with PE, women with a history of GH remain at an increased risk of developing HF later in life [118].

Peripartum cardiomyopathy (PPCM)

PPCM is a rare but life-threatening pregnancy-related cardiac disease which presents itself with HF secondary to LV dysfunction, either towards the end of pregnancy or within five months postpartum [119, 120]. The incidence of PPCM is approximately 1 in 1000–4000 live births in the USA and is diagnosed as an EF < 45% [8, 120]. While women often recover to normal cardiac function, long-lasting morbidity and mortality are present in up to 77% of PPCM patients [8, 121,122,123,124]. The exact etiology of PPCM is yet unknown; however, hormonal and vascular changes, as well as genetics seem to play a role [8]. Key features of PPCM pathophysiology include oxidative stress, endothelial dysfunction, angiogenic imbalance, and inflammatory reactions [125].

The anti-angiogenic 16-kDa N-terminal fragment of the nursing hormone prolactin (16 kDa-PRL) has been identified as a potential driving factor of PPCM [64]. Prolactin may be cleaved by cathepsin D [64]. Elevated serum levels of cathepsin D were found in PPCM patients and PPCM mouse models [64, 126]. Accordingly, 16 kDa-PRL levels are upregulated in the serum of PPCM patients and suppression of PRL secretion from the pituitary with the dopamine D2 receptor agonist bromocriptine had a beneficial effect in clinical trials on PPCM outcome [64, 127, 128]. How 16-kDa-PRL causes vascular dysfunction remains unclear, but is thought to involve inhibition of pro-angiogenic mediator plasminogen activator-1 (PAI-1) and regulation of miRNA expression [62, 129]. Enhanced 16-kDa-PRL levels in PPCM are thought to be caused by impaired activation of STAT3. Cardiomyocyte-specific STAT3-deficient mice develop PPCM [64]. Cardiac cathepsin D expression is elevated in these female STAT3-deficient mice, which is associated with enhanced production of 16-kDa-PRL. It was demonstrated that STAT3 deficiency led to diminished levels of mnSOD in cardiomyocytes, leading to increased oxidative stress that promotes the release of cathepsin D [64]. As a result, cardiomyocyte-specific STAT3-deficient female mice exhibited enhanced cardiac fibrosis, endothelial cell death, decreased cardiac capillary density and systolic dysfunction [64]. Importantly, decreased myocardial STAT3 expression was found concomitant with elevated serum cathepsin D and 16 kDa-PRL in PPCM patients [64].

Another factor participating in PPCM pathophysiology is the imbalance of pro-angiogenic VEGF and anti-angiogenic sFlt1 [125, 130]. The peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) is a transcriptional regulator of metabolic and angiogenic pathways in numerous tissues, including the heart [131]. Similar to STAT3 cardiac knockout mice, mice lacking PGC-1α in cardiomyocytes develop PPCM [130]. PGC-1α-deficient female mice exhibit decreased secretion of VEGF from cardiomyocytes, thus dramatically lowering the threshold for cardiac sFLT1 toxicity. Stimulation of sFLT1 caused enhanced systolic dysfunction in cardiomyocyte PGC-1α-deficient mice, while only affecting diastolic dysfunction in WT mice [130]. Importantly, plasma levels of sFLT were enhanced in PPCM patients compared to healthy pregnant women [130]. Additionally, part of PPCM pathophysiology is attributable to PGC-1α-deficiency causing mnSOD downregulation and thus elevated oxidative stress and cardiac capillary dysfunction [130].

Inflammation has also been proposed as a possible underlying mechanism of PPCM pathophysiology [125]. Elevated plasma levels of pro-inflammatory cytokines such as c-reactive protein (CRP), interleukin-6 (Il-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) have been found in PPCM patients and were shown to positively correlate with cardiac dysfunction [121, 126, 132].

Finally, a recent genetic study has identified 26 distinct truncating variants in eight genes in PPCM patients as compared to the reference population [133]. The majority of the identified truncating variants were in the titin gene and were observed in 10% of PPCM patients compared to ~ 1% in the reference population [133]. The sarcomeric protein, titin, contributes to homeostasis of sarcomere structure and is essential for coordinated cardiomyocyte contraction [134]. Interestingly, deleterious titin mutations have also been found in similar proportions in patients with idiopathic dilated cardiomyopathy [133].

Cardiac-related miRNAs in pregnancy-related cardiovascular complications

While up to 75% of the genome is transcribed into RNA, only 2% of the genome consists of protein-coding genes [15]. Consequently, non-coding RNAs, and in particular small non-coding miRNAs, have emerged as critical regulators of cellular processes in both health and disease [15]. In turn, many miRNAs are dynamically regulated by disease states. Indeed, numerous studies have shown changes in miRNA profiles during pregnancy with complications [17, 18]. Various cell types actively secrete miRNAs into the circulation, and thus can both mediate crosstalk between different cell-types or organs, and simultaneously represent disease biomarkers [135]. It has been shown that many miRNAs that are differentially expressed in maternal serum or plasma originate from the placenta [136, 137]. Since miRNAs are well-known to mediate various crucial processes in HF development [19], it is appealing to hypothesize that at least part of the cardiac dysfunction and HF pathophysiology in pregnancy-related complications may be mediated by miRNAs.

Dysregulated miRNAs in gestational diabetes mellitus

Several circulating miRNAs have been shown to be expressed differentially in patients with GDM. Here, we will discuss those miRNAs which have already been implicated in the pathophysiology of diabetic cardiomyopathy or other forms of adverse cardiac remodeling and HF (Fig. 1 and Table 1).

Fig. 1
figure 1

Dysregulated circulating cardiac-related miRNAs in cardiovascular complications during pregnancy. Depicted miRNAs have been shown to be involved in animal models of heart disease. GDM, gestational diabetes mellitus; GH, gestational hypertension; miR, microRNA; PE, preeclampsia; PPCM, peripartum cardiomyopathy

Table 1 Differentially expressed circulating miRNAs in gestational diabetes mellitus and their effects in heart disease

Serum miRNAs are expressed differentially per trimester between healthy pregnant and GDM patients [138]. In the first trimester, miR-125b-5p expression is shown to be elevated in the serum of GDM patients compared to healthy pregnant women and normalizes in the second and third trimesters [138]. Patients with acute myocardial infarction (MI) are reported to have elevated serum miR-125b-5p levels compared to controls [154]. However, in the mouse heart, miR-125b-5p was shown to play a role in protection against MI by repressing pro-apoptotic genes bak1 andLC3 (klf13) in cardiomyocytes [139]. Two cardio-protective miRs, namely, miR-183-5p and miR-200b-3p, are shown to be elevated in GDM serum compared with healthy pregnant control serum in the first trimester of pregnancy but become significantly downregulated by the third trimester [138]. Indeed, in the male rat heart, miR-183-5p was shown to protect against MI by repressing mitochondrial voltage-dependent anion channel 1 (VDAC1) leading to decreased apoptosis upon ischemia/reperfusion injury [140]. Interestingly, miR-200b-3p has been shown to protect against cardiac fibrosis and cardiac dysfunction in STZ-induced diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis via pro-fibrotic CD36 repression [141] and by inhibiting endothelial-to-mesenchymal transition [142].

Several studies have shown that plasma levels of miR-21-3p and miR-195-5p are upregulated in GDM patients compared to controls [143, 144, 146]. While not much is yet known about the role of miR-21-3p in diabetic cardiomyopathy thus far, miR-21-3p is shown to play a role in cardiac hypertrophy and HF. MiR-21-3p protects against cardiac hypertrophy in male mice by regulating histone deacetylase 8 (HDAC8) expression and Akt/Gsk3β signaling, important for growth control in the cardiovascular system [145]. It has been shown that miR-195-5p expression is upregulated in the hearts of STZ-induced diabetic cardiomyopathy in male mice [147]. Here, silencing of miR-195-5p in STZ mice led to enhanced expression of pro-survival mediators B cell lymphoma 2 (BCL-2) and sirtuin 1. Furthermore, cardiac hypertrophy, ROS, and apoptosis as measured by caspase 3 activity were reduced upon miR-195-5p silencing in male STZ mice, while myocardial capillary density and coronary blood flow were improved [147]. Similarly, miR-195-5p expression in rat cardiomyocytes is upregulated by high glucose stimulation [148]. Here, it was shown that silencing miR-195-5p rescues high-glucose-induced hERG potassium ion channel deficiency by restoring serum and glucocorticoid-regulated kinase 1 (SGK1) expression [148].

Expression levels of miR-29a and miR-222 are reported to be significantly reduced in the serum of GDM patients compared to healthy pregnant controls in similar gestational weeks [149]. The miR-29 family consists of 3 members; miR-29a, -b, and -c, and is well-known to be involved in diabetes mellitus and diabetic cardiomyopathy pathophysiology [155]. Interestingly, however, miR-29 levels are usually elevated in serum and several tissues of diabetic patients and animal models [155]. Cardiac miR-29a expression is elevated in male Zucker diabetic fatty (ZDF) rats compared to male Zucker lean rats and is concomitant with reduced expression of anti-apoptotic myeloid cell leukemia-1 (mcl-1) gene expression [150]. Furthermore, miR-29a has been shown to promote apoptosis in rat myocardial cells stimulated with high glucose by repressing insulin-like growth factor 1 (IGF-1) [151]. How these reports relate to reduced serum miR-29a levels in GDM patients remains to be elucidated. Reduced expression of miR-222 is shown in both patients and experimental models of adverse cardiac remodeling and HF [156, 157]. In male mice with diabetic cardiomyopathy, miR-222 has been shown to diminish cardiac fibrosis and improve cardiac function [156]. Here, miR-222 mainly acts by inhibiting endothelial-to-mesenchymal transition in the myocardial microvasculature by suppressing Wnt/β-catenin signaling. Furthermore, male mice with inducible cardiomyocyte-specific miR-222 overexpression are shown to be protected against ischemia-reperfusion injury by preserving cardiac structure and function while decreasing scar formation [152]. Here, miR-222 inhibits apoptosis by directly targeting cyclin-dependent kinase inhibitor p27, homeodomain interacting protein kinase 1 (HIPK1), and Hmbox-1 in cardiomyocytes [152]. In contrast, it has been reported that male mice overexpressing miR-222 in a cardiomyocyte-specific manner develop cardiac hypertrophy, fibrosis, and dysfunction with age [153]. Here, miR-222 represses p27, leading to activation of mTOR signaling and subsequent inhibition of autophagy.

Dysregulated miRNAs in preeclampsia and gestational hypertension

Numerous studies have shown differential expression of circulating miRNAs in pregnant females with PE, as has been reviewed previously [158, 159]. Here, we will focus on some of the prominent miRNAs that are known to play a role in adverse cardiac remodeling and HF (Fig. 1 and Table 2).

Table 2 Differentially expressed circulating miRNAs in preeclampsia and their effects in heart disease

Upregulated miRNAs in preeclampsia

Elevated circulating levels of both miR-210-3p and miR-210-5p have been found in PE patients in several studies [160,161,162,163]. MiR-210, a hypoxia-activated miRNA, is upregulated in the heart in pathological hypertrophy and HF [192]. Interestingly, however, miR-210 seems to be cardio-protective. In cardiomyocytes, Akt was shown to increase miR-210 expression leading to reduced ROS and cell death, most likely by targeting programmed cell death protein 4 (PDCD4) mechanism [164, 165]. Additionally, miR-210 inhibits cell-cycle inhibitor adenomatous polyposis coli (APC), and miR-210-overexpressing female mice exhibited reduced cardiomyocyte apoptosis, upregulated angiogenesis, and overall improvement in cardiac function after MI [166]. A similar effect was observed in exosome-derived miR-210 that inhibits the angiogenesis modulator ephrin A3 (Efna3), thus promoting cardiac angiogenesis after MI in male mice [167].

In contrast to the downregulation in GDM, plasma miR-29a is upregulated in mild PE compared to healthy pregnant controls [168]. The miR-29 family plays dual roles in cardiac remodeling and HF [155]. In patients with hypertrophic cardiomyopathy, plasma miR-29a was found to be upregulated and to positively correlate with both cardiac hypertrophy and fibrosis [169, 170]. In TAC-induced cardiac pressure overload in male mice, inhibition of miR-29a attenuated cardiac hypertrophy and fibrosis [170]. However, miR-29a has also been shown to protect against phenylephrine-induced cardiomyocyte hypertrophy by directly targeting the pro-hypertrophic NFATc4 [171].

Circulating levels of specific miRNAs in PE may be different based on disease severity. miR-21 and -155 have been shown to be elevated in the plasma of PE patients, upregulated approximately 5–8-fold in severe PE compared to mild PE [160]. While its role remains controversial, miR-21 is thought to be one of the most dysregulated and abundantly expressed miRNAs in hypertrophic and failing hearts [193]. Increased miR-21 expression has been shown to induce cardiomyocyte hypertrophy by mediating crosstalk between cardiac fibroblasts and cardiomyocytes. MiR-21 inhibits sprout homolog 1 (Spry1) in cardiac fibroblasts, enhancing ERK MAPK signaling, leading to enhanced cardiac fibrosis and cardiomyocyte hypertrophy upon TAC-induced cardiac pressure overload in male mice [172]. MiR-21 also promotes cardiac fibrosis after MI in male mice by directly targeting small mothers against decapentaplegic 7 (SMAD7), a negative regulator of the TGF-β1 signaling [173]. However, cardio-protective effects of miR-21 are also reported. In a male rat model of cardiac ischemia/reperfusion, miRNA-21 protected against cardiomyocyte apoptosis by targeting PDCD4 [174]. In male mice, miR-21 attenuated cardiac dysfunction and inflammatory signaling after MI by directly targeting kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), a modulator of p38 MAPK and NFκB signaling [175]. MiR-155 is a key mediator of cardiac inflammation and hypertrophy. MiR-155-deficient mice exhibited dampened cardiac hypertrophy upon TAC-induced pressure overload, most likely by relieving miR-155-induced inhibition of histone demethylase jumonji, AT rich interactive domain 2 (Jarid2) [176]. Loss of miR-155 in macrophages was shown to promote cardiomyocyte hypertrophy in a paracrine manner in male mice [177]. Here, miR-155 directly targets pro-hypertrophic suppressor of cytokine signaling 1 (Socs1). Additionally, miR-155 deficiency in male fibroblasts improved cardiac function and remodeling after MI through targeting tumor protein p-53-inducible nuclear protein 1 (TP53INP1) gene [178].

Interestingly, differences in circulating miRNA expression already before the onset of clinical symptoms may be predictive of PE development. Plasma miR-206 was upregulated in asymptomatic patients in the early third trimester who later developed PE compared to those who had a healthy pregnancy [179]. In male mice, miR-206 was shown to exacerbate TAC-induced cardiac hypertrophy by targeting tumor suppressor, Forkhead box protein P1 (FoxP1) [180]. Whether circulating miR-206 remains differentially expressed at the time of clinical PE manifestation remains to be elucidated.

Downregulated miRNAs in preeclampsia

Multiple studies have found plasma and serum miR-144 levels to be downregulated in PE patients compared to healthy controls, in various stages of disease progression [160, 161, 168]. Loss of miR-144 in male mice was shown to lead to impaired extracellular matrix remodeling after MI, leading to cardiac dysfunction. Here, miR-144 targets zinc finger E-box binding homeobox 1 (Zeb-1), a mediator of mesenchymal transition important for a proper fibrotic response after injury [181]. Conversely, injection of miR-144 mimics improved cardiac function after MI in mice by reducing fibrosis, inflammation, and apoptosis [182]. Additionally, loss of miR-144 in male mice enhances injury after MI by targeting Ras-related C3 botulinum toxin substrate 1 (Rac-1), a key component of NADPH oxidase, which results in elevated ROS levels [183].

In contrast to observed upregulation in GDM, plasma miR-125b-5p and miR-195-5p are shown to be downregulated in severe PE compared to healthy controls [184, 185]. However, elevated plasma miR-195-5p has also been reported in PE patients, where it positively correlates with sFLT1 levels [186]. In male mice, miR-195-5p promotes Angiotensin II-induced cardiomyocyte hypertrophy by targeting its downstream targets, tumor suppressor FBXW7, and mitofusin 2 (MFN2), which are known to inhibit mitochondrial membrane depolarization and ROS production [187].

Strikingly, differences in circulating miRNA expression levels before clinical PE symptoms are apparent may be predictive of future disease. Serum levels of miR-126, miR-204, and miR-15b in early gestation were found to be downregulated in women who developed severe PE in the third trimester, compared to women who developed a healthy pregnancy [161]. Endothelial cell and vascular integrity are regulated by miR-126. It was demonstrated that miR-126 represses the anti-angiogenic modulator sprouty-related, EVH1 domain-containing protein 1 (Spred1), leading to defective angiogenesis after MI in miR-126-deficient mice [188]. Furthermore, miR-126 protects human cardiac microvascular endothelial cells against hypoxia/reoxygenation injury by activating PI3K/Akt signaling and increasing VEGF and SOD expression [189]. MiR-204 seems to play a role in autophagy modulation. It was demonstrated that miR-204 may target cardiomyocyte microtubule-associated protein 1 light chain 3 (LC3-II), which is important for autophagosome formation, in cardiac ischemia/reperfusion injury in rats [190]. Lastly, miR-15b was demonstrated to inhibit several components of the TGFβ signaling pathway in cardiomyocytes including p38 MAPK and TGFβ receptor 1 (TGFβR-1), with in vivo miR-15b antagonism leading to enhanced cardiomyocyte hypertrophy and fibrosis upon TAC-induced pressure overload in mice [191].

Dysregulated miRNAs in gestational hypertension

GH and PE are related but distinct disorders, which is reflected in the circulating miRNA profile of PE and GH patients (Fig. 1 and Table 3). For instance, serum levels of miR-29a were shown to be increased in both PE patients and GH patients compared with normotensive patients [194]. Furthermore, plasma miR-125b-5p was downregulated in both PE and GH patients [184]. Interestingly, however, serum miR-181a was shown to be elevated in GH patients compared to normotensive and PE patients, in whom no difference in serum miR-181a levels was found [194]. It has been reported that miR-181a plays several roles in HF. Elevated plasma miR-181a has been suggested to be a marker of acute MI, where miR-181a levels positively correlate with the oxidative stress marker lipid hydroperoxide [195]. In a male rat model of MI, cardiac miR-181a expression increases over time and was shown to be associated with enhanced expression of the extracellular matrix components collagen I and fibronectin by directly targeting the anti-fibrotic TGF-β type III receptor in cardiac fibroblasts [196]. However, in a rat model of pressure overload cardiac hypertrophy via abdominal aortic constriction, cardiac miR-181a was reported to be downregulated. Downregulation of miR-181a in cardiomyocytes led to enhanced hypertrophy due to enhanced autophagy and expression of miR-181a target autophagy-mediated protein 5 (ATG5) [197].

Table 3 Differentially expressed circulating miRNAs in gestational hypertension and their effects in heart disease

Dysregulated miRNAs in peripartum cardiomyopathy

While not many differentially-expressed circulating miRNAs have been identified in PPCM, the miRNAs that are known have directly been shown to contribute to PPCM cardiac pathophysiology (Fig. 1 and Table 4).

Table 4 Differentially expressed miRNAs in peripartum cardiomyopathy

In plasma, serum, and myocardium of PPCM patients, miR-146a is well-known to be elevated [62, 198]. PPCM-associated anti-angiogenic 16kDa-PRL induces miR-146a expression via NFκB in endothelial cells [62]. It has been shown that miR-146a inhibits proliferation and enhances apoptosis of endothelial cells by repressing the proto-oncogene neuroblastoma RAS viral oncogene homolog (NRAS) [62]. Additionally, miR-146a is packed into endothelial cell-derived exosomes which can be taken up by cardiomyocytes [62]. In cardiomyocytes, miR-146a dampens metabolic activity through inhibition of receptor tyrosine-protein kinase erbB-4 (ERBB4), an important modulator of physiological pregnancy-induced cardiac hypertrophy [62]. Indeed, in both the STAT3-deficient PPCM female mouse model and PPCM patients, miR-146a is upregulated while ERBB4 expression is decreased compared to healthy controls [62].

Besides miR-146a, in the LV of STAT3-deficient PPCM male mice and PPCM patients miR-199a-5p was found to be upregulated [61, 199]. Here, decreased STAT3 levels induced miR-199a-5p-mediated ERBB4 inhibition in cardiomyocytes, leading to reduced glucose uptake by the heart, ROS production and cell death [199]. Furthermore, decreased STAT3 levels in cardiomyocytes were shown to induce miR-199a-5p-mediated repression of the ubiquitin-proteasome system (UPS) by repressing ubiquitin-conjugating enzymes Ube2g1 and Ube2i [61]. This ultimately leads to cardiomyocyte sarcomere disarray. Additionally, miR-199a-5p-mediated UPS dysfunction leads to enhanced secretion of asymmetric dimethylarginine (ADMA) from cardiomyocytes. In turn, secreted ADMA lowers nitric oxide bioavailability for cardiac endothelial cells, leading to endothelial dysfunction and apoptosis [61].

Future perspectives and concluding remarks

In this review, we summarize current knowledge on pregnancy-related cardiovascular complications that may lead to cardiac dysfunction during pregnancy in previously healthy women, emphasizing the possible role of miRNAs in the cardiac pathophysiology of these complications.

Since about 12% of pregnancy-related deaths in the USA have been attributed to HF, and since GDM, PE, GH, and PPCM have been associated with a short- and long-term risk of HF development and death, there is a necessity for novel diagnostic and prognostic markers and therapeutic targets [9,10,11,12]. Circulating miRNAs have been proposed to fulfill these needs in both cardiac dysfunction and pregnancy-related complications [159, 200]. While the mounting data on circulating miRNA expression in pregnancy complications is promising, some discrepancies exist between studies. Such discrepancies may be due to differences in isolation and profiling of miRNAs either from plasma or serum, population characteristics, gestational age, internal controls, or normalization methods [159, 200].

Connecting circulating miRNAs in pregnancy-related cardiovascular complications to adverse cardiac remodeling and dysfunction in pregnancy remains understudied and further research needs to be conducted. However, several hurdles must be overcome. Firstly, all but a few studies have not directly linked circulating miRNAs to cardiac pathology since human cardiac tissue samples from pregnant women are scarce. Therefore, animal models provide an attractive alternative to further study the mechanisms and therapeutics of cardiovascular complications and HF in pregnancy. Although rodent pregnancies differ vastly from human pregnancies and not all aspects of human pregnancy can be translated in rodents, both do have similar cardiovascular adaptations to pregnancy [201]. Secondly, the majority of mechanistic studies into the roles of miRNAs in cardiac dysfunction have been performed in male animals. A growing body of evidence points towards differences in miRNA regulation of cardiac remodeling and HF between males and females [202, 203], thus posing an extra translational hurdle into the role of miRNA in cardiac remodeling and HF in pregnant females. Thirdly, miRNAs have been shown to exert opposite effects on cardiomyocytes and cardiac fibroblasts, leading to varied disease outcomes [155, 193]. Therefore, it is important to delineate from which cell-types the altered circulating miRNAs in pregnancy complications originate and on which cardiac cell types their modulatory effects are the largest. Lastly, differences in circulating miRNA expression already before the onset of clinical symptoms have been reported in PE [161, 179]. Focusing on such early-response miRNAs will aid in developing true prognostic biomarkers for pregnancy-related heart disease.

Perspectives and significance

While existing data from different heart disease models are promising, further investigation is needed to directly and causally link miRNAs to cardiac pathophysiology in cardiovascular complications of pregnancy, which will aid in improved diagnosis and development of novel therapies.

Availability of data and materials

Not applicable.



16-kDa N-terminal fragment of prolactin


3′ untranslated region


Asymmetric dimethylarginine


Protein kinase B


Adenomatous polyposis coli


Autophagy-mediated protein 5


BCcell lymphoma 2


C-reactive protein


Ejection fraction


Ephrin A3


Receptor tyrosine-protein kinase erbB-4


Extracellular signal-regulated kinase


Forkhead box protein P1


Gestational diabetes mellitus


Gestational hypertension


Glucose transporter 4


Glycogen synthase kinase 3β


Histone deacetylase 8


Human ether-a-go-go-related gene


Heart failure


Homeodomain interacting protein kinase 1


Interferon γ


Insulin-like growth factor 1




Demethylase jumonji, AT rich interactive domain 2


c-Jun N-terminal


Kelch repeat and BTB (POZ) domain containing 7


Kruppel-like factor 13


Microtubule-associated protein 1 light chain 3


Left ventricle


Mitogen-activated protein kinase


Myeloid cell leukemia-1


Mitogen-activated protein kinase 1


Mitofusion 2


Myocardial infarction




Mitochondrial superoxide dismutase


Mammalian target of rapamycin


Nuclear factor of activated T-cells


Nuclear factor kappa-light-chain-enhancer of activated B cells


Oncogene neuroblastoma RAS viral oncogene homolog


Ribosomal S6 protein kinase


Plasminogen activator-1


Programmed cell death protein 4




Peroxisome proliferator-activated receptor gamma coactivator 1-alpha




Peripartum cardiomyopathy


Ras-related C3 botulinum toxin substrate 1


Reactive oxygen species


Soluble endoglin


Soluble fms-like tyrosine kinase-1


Serum and glucocorticoid-regulated kinase 1


Small mothers against decapentaplegic 7


Sympathetic nervous system


Suppressor of cytokine signaling 1


Sprouty-related, EVH1 domain-containing protein 1


Sprout homolog 1


Signal transducer and activator of transcription 3


Storkhead box 1




Transverse aortic constriction


Transforming growth factor-β1


Transforming growth factor-β receptor type I


Tumor necrosis factor α


Tumor protein p-53-inducible nuclear protein 1


Ubiquitin-proteasome system


Voltage-dependent anion channel 1


Vascular endothelial growth factor




Zucker diabetic fatty rat


Zinc finger E-box binding homeobox 1


  1. Monika S, Rutherford John D. Cardiovascular physiology of pregnancy. Circulation. 2014;130(12):1003–8.

    Article  Google Scholar 

  2. Mogos MF, Piano MR, McFarlin BL, Salemi JL, Liese KL, Briller JE. Heart failure in pregnant women. Circulation. 2018;11(1):e004005.

    PubMed  Google Scholar 

  3. Graves CR, Davis SF. Cardiovascular complications in pregnancy. Circulation. 2018;137(12):1213–5.

    Article  PubMed  Google Scholar 

  4. Anthony J, Sliwa K. Decompensated heart failure in pregnancy. Card Fail Rev. 2016;2(1):20–6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Appiah D, Schreiner PJ, Gunderson EP, Konety SH, Jacobs DR Jr, Nwabuo CC, et al. Association of gestational diabetes mellitus with left ventricular structure and function: the CARDIA Study. Diabetes Care. 2016;39(3):400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Melchiorre K, Thilaganathan B. Maternal cardiac function in preeclampsia. Curr Opin Obstet Gynecol. 2011;23(6):440–7.

    Article  PubMed  Google Scholar 

  7. Castleman JS, Ramesh G, Fatima T, Lip Gregory YH, Steeds Richard P, Dipak K. Echocardiographic structure and function in hypertensive disorders of pregnancy. Circulation. 2016;9(9):e004888.

    PubMed  Google Scholar 

  8. Arany Z. Understanding peripartum cardiomyopathy. Annu Rev Med. 2018;69(1):165–76.

    Article  CAS  PubMed  Google Scholar 

  9. Creanga A, Berg C, Syverson C, Seed K, Bruce F, Callaghan W. Pregnancy-related mortality in the United States, 2006–2010. Obstet Gynecol. 2015;125(1):5–12.

    Article  PubMed  Google Scholar 

  10. Ng AT, Duan L, Win T, Spencer HT, Lee M-S. Maternal and fetal outcomes in pregnant women with heart failure. Heart. 2018;104(23):1949–54.

    Article  PubMed  Google Scholar 

  11. Wu P, Randula H, Shing KC, Aswin B, Kotronias Rafail A, Claire R, et al. Preeclampsia and future cardiovascular health. Circulation. 2017;10(2):e003497.

    PubMed  Google Scholar 

  12. Damm P, Houshmand-Oeregaard A, Kelstrup L, Lauenborg J, Mathiesen ER, Clausen TD. Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark. Diabetologia. 2016;59(7):1396–9.

    Article  CAS  PubMed  Google Scholar 

  13. Liu LX, Arany Z. Maternal cardiac metabolism in pregnancy. Cardiovasc Res. 2014;101(4):545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc Pathol. 2012;21(5):365–71.

    Article  CAS  PubMed  Google Scholar 

  15. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. McCreight JC, Schneider SE, Wilburn DB, Swanson WJ. Evolution of microRNA in primates. PLoS One. 2017;12(6):e0176596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Morales-Prieto DM, Ospina-Prieto S, Chaiwangyen W, Schoenleben M, Markert UR. Pregnancy-associated miRNA-clusters. J Reprod Immunol. 2013;97(1):51–61.

    Article  CAS  PubMed  Google Scholar 

  18. Cai M, Kolluru GK, Ahmed A. Small molecule, big prospects: microRNA in pregnancy and its complications. J Pregnancy. 2017;2017:6972732.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469(7330):336–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang Y-M, Huang Y-M, Li W-W, Li W-W, Wu J, Wu J, et al. The diagnostic value of circulating microRNAs in heart failure (Review). Exp Ther Med. 2019;17(3):1985–2003.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hall ME, George EM, Granger JP. The heart during pregnancy. Rev Esp Cardiol. 2011;64(11):1045–50.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Soma-Pillay P, Nelson-Piercy C, Tolppanen H, Mebazaa A. Physiological changes in pregnancy. Cardiovasc J Afr. 2016;27(2):89–94.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li J, Umar S, Amjedi M, Iorga A, Sharma S, Nadadur RD, et al. New frontiers in heart hypertrophy during pregnancy. Am J Cardiovasc Dis. 2012;2(3):192–207.

    PubMed  PubMed Central  Google Scholar 

  24. Chung E, Leinwand LA. Pregnancy as a cardiac stress model. Cardiovasc Res. 2014;101(4):561–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016;97:245–62.

    Article  CAS  PubMed  Google Scholar 

  26. Umar S, Nadadur R, Iorga A, Amjedi M, Matori H, Eghbali M. Cardiac structural and hemodynamic changes associated with physiological heart hypertrophy of pregnancy are reversed postpartum. J Appl Physiol (1985). 2012;113(8):1253–9.

    Article  Google Scholar 

  27. Maack C, Lehrke M, Backs J, Heinzel FR, Hulot J-S, Marx N, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association–European Society of Cardiology. Eur Heart J. 2018;39(48):4243–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu LX, Rowe GC, Yang S, Li J, Damilano F, Chan MC, et al. PDK4 inhibits cardiac pyruvate oxidation in late pregnancy. Circ Res. 2017;121(12):1370–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Redondo-Angulo I, Mas-Stachurska A, Sitges M, Tinahones FJ, Giralt M, Villarroya F, et al. Fgf21 is required for cardiac remodeling in pregnancy. Cardiovasc Res. 2017;113(13):1574–84.

    Article  CAS  PubMed  Google Scholar 

  30. Williams JG, Ojaimi C, Qanud K, Zhang S, Xu X, Recchia FA, et al. Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog. Am J Physiol Heart Circ Physiol. 2008;294(6):H2516–23.

    Article  CAS  PubMed  Google Scholar 

  31. Rimbaud S, Sanchez H, Garnier A, Fortin D, Bigard X, Veksler V, et al. Stimulus specific changes of energy metabolism in hypertrophied heart. J Mol Cell Cardiol. 2009;46(6):952–9.

    Article  CAS  PubMed  Google Scholar 

  32. Chokshi A, Drosatos K, Cheema FH, Ji R, Khawaja T, Yu S, et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation. 2012;125(23):2844–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Garnier A, Fortin D, Deloménie C, Momken I, Veksler V, Ventura-Clapier R. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol Lond. 2003;551(Pt 2):491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chung E, Yeung F, Leinwand LA. Akt and MAPK signaling mediate pregnancy-induced cardiac adaptation. J Appl Physiol (1985). 2012;112(9):1564–75.

    Article  CAS  Google Scholar 

  35. Haghikia A, Stapel B, Hoch M, Hilfiker-Kleiner D. STAT3 and cardiac remodeling. Heart Fail Rev. 2011;16(1):35–47.

    Article  CAS  PubMed  Google Scholar 

  36. Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, et al. Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2002;99(2):907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shioi T, Kang PM, Douglas PS, Hampe J, Yballe CM, Lawitts J, et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 2000;19(11):2537–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM, et al. Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci U S A. 2003;100(21):12355–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brian DB, Iya T, Lupu TS, Carla W, Attila K, Michael C, et al. Akt1 is required for physiological cardiac growth. Circulation. 2006;113(17):2097–104.

    Article  CAS  Google Scholar 

  40. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, et al. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A. 2002;99(19):12333–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Skurk C, Izumiya Y, Maatz H, Razeghi P, Shiojima I, Sandri M, et al. The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem. 2005;280(21):20814–23.

    Article  CAS  PubMed  Google Scholar 

  42. Lemmens K, Doggen K, De Keulenaer GW. Activation of the neuregulin/ErbB system during physiological ventricular remodeling in pregnancy. Am J Physiol Heart Circ Physiol. 2010;300(3):H931–42.

    Article  PubMed  CAS  Google Scholar 

  43. Gonzalez AMD, Osorio JC, Manlhiot C, Gruber D, Homma S, Mital S. Hypertrophy signaling during peripartum cardiac remodeling. Am J Physiol Heart Circ Physiol. 2007;293(5):H3008–13.

    Article  CAS  PubMed  Google Scholar 

  44. Saito T, Ciobotaru A, Bopassa JC, Toro L, Stefani E, Eghbali M. Estrogen contributes to gender differences in mouse ventricular repolarization. Circ Res. 2009;105(4):343–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Improta-Brears T, Whorton AR, Codazzi F, York JD, Meyer T, McDonnell DP. Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium. Proc Natl Acad Sci U S A. 1999;96(8):4686–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kazi AA, Molitoris KH, Koos RD. Estrogen rapidly activates the PI3K/AKT pathway and hypoxia-inducible factor 1 and induces vascular endothelial growth factor A expression in luminal epithelial cells of the rat uterus. Biol Reprod. 2009;81(2):378–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mansoureh E, Rupal D, Abderrahmane A, Minosyan TY, Hongmei R, Wang Y, et al. Molecular and functional signature of heart hypertrophy during pregnancy. Circ Res. 2005;96(11):1208–16.

    Article  CAS  Google Scholar 

  48. Torsoni AS, Constancio SS, Wilson N, Hanks Steven K, Franchini Kleber G. Focal adhesion kinase is activated and mediates the early hypertrophic response to stretch in cardiac myocytes. Circ Res. 2003;93(2):140–7.

    Article  CAS  PubMed  Google Scholar 

  49. Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev. 2010;90(4) Available from: [cited 2019 Dec 19].

  50. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, et al. The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 2000;19(23):6341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yamaguchi O, Higuchi Y, Hirotani S, Kashiwase K, Nakayama H, Hikoso S, et al. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc Natl Acad Sci U S A. 2003;100(26):15883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Haq S, Choukroun G, Lim H, Tymitz KM, del Monte F, Gwathmey J, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation. 2001;103(5):670–7.

    Article  CAS  PubMed  Google Scholar 

  53. Parra V, Rothermel BA. Calcineurin signaling in the heart: the importance of time and place. J Mol Cell Cardiol. 2017;103:121–36.

    Article  CAS  PubMed  Google Scholar 

  54. Chung E, Yeung F, Leinwand LA. Calcineurin activity is required for cardiac remodelling in pregnancy. Cardiovasc Res. 2013;100(3):402–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Harhous Z, Booz GW, Ovize M, Bidaux G, Kurdi M. An update on the multifaceted roles of STAT3 in the heart. Front Cardiovasc Med. 2019;6 Available from: [cited 2019 Dec 20].

  56. Zouein FA, Altara R, Chen Q, Lesnefsky EJ, Kurdi M, Booz GW. Pivotal importance of STAT3 in protecting the heart from acute and chronic stress: new advancement and unresolved issues. Front Cardiovasc Med. 2015;2:36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Murray PJ. STAT3-mediated anti-inflammatory signalling. Biochem Soc Trans. 2006;34(Pt 6):1028–31.

    Article  CAS  PubMed  Google Scholar 

  58. Zgheib C, Zouein FA, Kurdi M, Booz GW. Differential STAT3 signaling in the heart: Impact of concurrent signals and oxidative stress. JAKSTAT. 2012;1(2):101–10.

    PubMed  PubMed Central  Google Scholar 

  59. Datta R, Bansal T, Rana S, Datta K, Datta Chaudhuri R, Chawla-Sarkar M, et al. Myocyte-derived Hsp90 modulates collagen upregulation via biphasic activation of STAT-3 in fibroblasts during cardiac hypertrophy. Mol Cell Biol. 2017;37(6):e00611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Meléndez GC, McLarty JL, Levick SP, Du Y, Janicki JS, Brower GL. Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension. 2010;56(2):225–31.

    Article  PubMed  CAS  Google Scholar 

  61. Haghikia A, Missol-Kolka E, Tsikas D, Venturini L, Brundiers S, Castoldi M, et al. Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes. Eur Heart J. 2010;32(10):1287–97.

    Article  PubMed  CAS  Google Scholar 

  62. Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen N-Q-N, Scherr M, et al. MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Invest. 2013;123(5):2143–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shinji N, Keita K, Yasushi F, Masanobu F, Darville MI, Eizirik DL, et al. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation. 2001;104(9):979–81.

    Article  Google Scholar 

  64. Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell. 2007;128(3):589–600.

    Article  CAS  PubMed  Google Scholar 

  65. Li J, Ruffenach G, Kararigas G, Cunningham CM, Motayagheni N, Barakai N, et al. Intralipid protects the heart in late pregnancy against ischemia/reperfusion injury via Caveolin2/STAT3/GSK-3β pathway. J Mol Cell Cardiol. 2017;102:108–16.

    Article  CAS  PubMed  Google Scholar 

  66. Li J, Umar S, Iorga A, Youn J-Y, Wang Y, Regitz-Zagrosek V, et al. Cardiac vulnerability to ischemia/reperfusion injury drastically increases in late pregnancy. Basic Res Cardiol. 2012;107(4):271.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Ricke-Hoch M, Bultmann I, Stapel B, Condorelli G, Rinas U, Sliwa K, et al. Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress. Cardiovasc Res. 2014;101(4):587–96.

    Article  CAS  PubMed  Google Scholar 

  68. Sarosh R, Elizabeth L, Granger Joey P, Ananth KS. Preeclampsia. Circ Res. 2019;124(7):1094–112.

    Article  CAS  Google Scholar 

  69. Angueira AR, Ludvik AE, Reddy TE, Wicksteed B, Lowe WL Jr, Layden BT. New insights into gestational glucose metabolism: lessons learned from 21st century approaches. Diabetes. 2015;64(2):327–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sullivan SD, Umans JG, Ratner R. Gestational diabetes: implications for cardiovascular health. Curr Diab Rep. 2012;12(1):43–52.

    Article  CAS  PubMed  Google Scholar 

  71. Melenovsky V, Benes J, Franekova J, Kovar J, Borlaug BA, Segetova M, et al. Glucose homeostasis, pancreatic endocrine function, and outcomes in advanced heart failure. J Am Heart Assoc. 2017;6(8):e005290.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Freire CMV, do Carmo Pereira Nunes M, Melo Barbosa M, Ribeiro de Oliveira Longo J, Impeliziere Nogueira A, Santos Assreuy Diniz S, et al. Gestational diabetes: a condition of early diastolic abnormalities in young women. J Am Soc Echocardiogr. 2006;19(10):1251–6.

    Article  PubMed  Google Scholar 

  73. McKenzie-Sampson S, Paradis G, Healy-Profitós J, St-Pierre F, Auger N. Gestational diabetes and risk of cardiovascular disease up to 25 years after pregnancy: a retrospective cohort study. Acta Diabetol. 2018;55(4):315–22.

    Article  PubMed  Google Scholar 

  74. Savitz DA, Danilack VA, Elston B, Lipkind HS. Pregnancy-induced hypertension and diabetes and the risk of cardiovascular disease, stroke, and diabetes hospitalization in the year following delivery. Am J Epidemiol. 2014;180(1):41–4.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kessous R, Shoham-Vardi I, Pariente G, Sherf M, Sheiner E. An association between gestational diabetes mellitus and long-term maternal cardiovascular morbidity. Heart. 2013;99(15):1118–21.

    Article  PubMed  Google Scholar 

  76. Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci. 2018;19(11):3342.

    Article  PubMed Central  CAS  Google Scholar 

  77. Catalano PM. Trying to understand gestational diabetes. Diabet Med. 2014;31(3):273–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Imoh LC, Ocheke AN. Correlation between maternal weight and insulin resistance in second half of pregnancy. Niger Med J. 2014;55(6):465–8.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. 2007;30(Supplement 2):S112.

    Article  CAS  PubMed  Google Scholar 

  80. Moyce BL, Dolinsky VW. Maternal β-cell adaptations in pregnancy and placental signalling: implications for gestational diabetes. Int J Mol Sci. 2018;19(11) Available from: [cited 2019 Dec 30].

  81. Yang Y, Lixiu L, Liu B, Li Q, Wang Z, Fan S, et al. Functional defects of regulatory T cell through interleukin 10 mediated mechanism in the induction of gestational diabetes mellitus. DNA Cell Biol. 2018;37(3):278–85.

    Article  CAS  PubMed  Google Scholar 

  82. Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes. 2007;56(9):2356.

    Article  CAS  PubMed  Google Scholar 

  83. Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000;71(5):1256S–61S.

    Article  CAS  PubMed  Google Scholar 

  84. Di Cianni G, Miccoli R, Volpe L, Lencioni C, Del Prato S. Intermediate metabolism in normal pregnancy and in gestational diabetes. Diabetes Metab Res Rev. 2003;19(4):259–70.

    Article  PubMed  CAS  Google Scholar 

  85. Liu Y, Zhao J, Lu M, Wang H, Tang F. Retinoic acid attenuates cardiac injury induced by hyperglycemia in pre- and post-delivery mice. Can J Physiol Pharmacol. 2020;98(1):6–14.

  86. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014;57(4):660–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Braunthal S, Brateanu A. Hypertension in pregnancy: pathophysiology and treatment. SAGE Open Med. 2019;7:2050312119843700.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Mammaro A, Carrara S, Cavaliere A, Ermito S, Dinatale A, Pappalardo EM, et al. Hypertensive disorders of pregnancy. J Prenat Med. 2009;3(1):1–5.

    PubMed  PubMed Central  Google Scholar 

  89. Wendy Y, Catov Janet M, Pamela O. Hypertensive disorders of pregnancy and future maternal cardiovascular risk. J Am Heart Assoc. 2018;7(17):e009382.

    Google Scholar 

  90. Vaught AJ, Kovell LC, Szymanski LM, Mayer SA, Seifert SM, Vaidya D, et al. Acute cardiac effects of severe pre-eclampsia. J Am Coll Cardiol. 2018;72(1):1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Visser W, Wallenburg HC. Central hemodynamic observations in untreated preeclamptic patients. Hypertension. 1991;17(6_pt_2):1072–7.

    Article  CAS  PubMed  Google Scholar 

  92. Basky T, Erkan K. Cardiovascular system in preeclampsia and beyond. Hypertension. 2019;73(3):522–31.

    Article  CAS  Google Scholar 

  93. Lang RM, Pridjian G, Feldman T, Neumann A, Lindheimer M, Borow KM. Left ventricular mechanics in preeclampsia. Am Heart J. 1991;121(6, Part 1):1768–75.

    Article  CAS  PubMed  Google Scholar 

  94. Simmons LA, Gillin AG, Jeremy RW. Structural and functional changes in left ventricle during normotensive and preeclamptic pregnancy. Am J Physiol Heart Circ Physiol. 2002;283(4):H1627–33.

    Article  CAS  PubMed  Google Scholar 

  95. Shivananjiah C, Nayak A, Swarup A. Echo changes in hypertensive disorder of pregnancy. J Cardiovasc Echogr. 2016;26(3):94–6.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Melchiorre K, Sutherland GR, Baltabaeva A, Liberati M, Thilaganathan B. Maternal cardiac dysfunction and remodeling in women with preeclampsia at term. Hypertension. 2011;57(1):85–93.

    Article  CAS  PubMed  Google Scholar 

  97. Melchiorre K, Sutherland GR, Watt-Coote I, Liberati M, Thilaganathan B. Severe myocardial impairment and chamber dysfunction in preterm preeclampsia. Hypertens Pregnancy. 2012;31(4):454–71.

    Article  PubMed  Google Scholar 

  98. Borges VTM, Zanati SG, Peraçoli MTS, Poiati JR, Romão-Veiga M, Peraçoli JC, et al. Maternal left ventricular hypertrophy and diastolic dysfunction and brain natriuretic peptide concentration in early- and late-onset pre-eclampsia. Ultrasound Obstet Gynecol. 2018;51(4):519–23.

    Article  CAS  PubMed  Google Scholar 

  99. Veerbeek JHW, Hermes W, Breimer AY, van Rijn BB, Koenen SV, Mol BW, et al. Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension. Hypertension. 2015;65(3):600–6.

    Article  CAS  PubMed  Google Scholar 

  100. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993;90(22):10705–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Levine RJ, Maynard SE, Qian C, Lim K-H, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83.

    Article  CAS  PubMed  Google Scholar 

  102. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12(6):642–9.

    Article  CAS  PubMed  Google Scholar 

  103. Regal JF, Burwick RM, Fleming SD. The complement system and preeclampsia. Curr Hypertens Rep. 2017;19(11):87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Chen W, Qian L, Wu F, Li M, Wang H. Significance of toll-like receptor 4 signaling in peripheral blood monocytes of pre-eclamptic patients. Hypertens Pregnancy. 2015;34(4):486–94.

    Article  CAS  PubMed  Google Scholar 

  105. Irani RA, Xia Y. The functional role of the renin–angiotensin system in pregnancy and preeclampsia. Placenta. 2008;29(9):763–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Reyes LM, Usselman CW, Davenport MH, Steinback CD. Sympathetic nervous system regulation in human normotensive and hypertensive pregnancies. Hypertension. 2018;71(5):793–803.

    Article  CAS  PubMed  Google Scholar 

  107. Hibbard JU, Shroff SG, Lang RM. Cardiovascular changes in preeclampsia. Semin Nephrol. 2004;24(6):580–7.

    Article  PubMed  Google Scholar 

  108. Cui Y, Wang W, Dong N, Lou J, Srinivasan DK, Cheng W, et al. Role of corin in trophoblast invasion and uterine spiral artery remodeling in pregnancy. Nature. 2012;484(7393):246–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. van Dijk M, Mulders J, Poutsma A, Könst AAM, Lachmeijer AMA, Dekker GA, et al. Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family. Nat Genet. 2005;37(5):514–9.

    Article  PubMed  CAS  Google Scholar 

  110. Baird RC, Li S, Wang H, Naga Prasad SV, Majdalany D, Perni U, et al. Pregnancy-associated cardiac hypertrophy in corin-deficient mice: observations in a transgenic model of preeclampsia. Can J Cardiol. 2019;35(1):68–76.

    Article  PubMed  Google Scholar 

  111. Ducat A, Doridot L, Calicchio R, Méhats C, Vilotte J-L, Castille J, et al. Endothelial cell dysfunction and cardiac hypertrophy in the STOX1 model of preeclampsia. Sci Rep. 2016;6:19196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tangerås LH, Austdal M, Skråstad RB, Salvesen KÅ, Austgulen R, Bathen TF, et al. Distinct first trimester cytokine profiles for gestational hypertension and preeclampsia. Arterioscler Thromb Vasc Biol. 2015;35(11):2478–85.

    Article  PubMed  CAS  Google Scholar 

  113. Herbert V, Paolo NG, Barbara V, Giancarlo DR, Elisabetta RM, Massimo M, et al. Maternal diastolic dysfunction and left ventricular geometry in gestational hypertension. Hypertension. 2001;37(5):1209–15.

    Article  Google Scholar 

  114. Blanco MV, Roisinblit J, Grosso O, Rodriguez G, Robert S, Berensztein CS, et al. Left ventricular function impairment in pregnancy-induced hypertension. Am J Hypertens. 2001;14(3):271–5.

    Article  Google Scholar 

  115. Cho K-I, Kim S-M, Shin M-S, Kim E-J, Cho E-J, Seo H-S, et al. Impact of gestational hypertension on left ventricular function and geometric pattern. Circ J. 2011;75(5):1170–6.

    Article  PubMed  Google Scholar 

  116. Vlahović-Stipac A, Stankić V, Popović ZB, Putniković B, Nešković AN. Left ventricular function in gestational hypertension: serial echocardiographic study. Am J Hypertens. 2010;23(1):85–91.

    Article  PubMed  Google Scholar 

  117. Scantlebury DC, Kane GC, Wiste HJ, Bailey KR, Turner ST, Arnett DK, et al. Left ventricular hypertrophy after hypertensive pregnancy disorders. Heart. 2015;101(19):1584–90.

    Article  CAS  PubMed  Google Scholar 

  118. Männistö T, Mendola P, Vääräsmäki M, Järvelin M-R, Hartikainen A-L, Pouta A, et al. Elevated blood pressure in pregnancy and subsequent chronic disease risk. Circulation. 2013;127(6):681–90.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, Blomström-Lundqvist C, Cífková R, De Bonis M, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39(34):3165–241.

    Article  PubMed  Google Scholar 

  120. Zolt A, Uri E. Peripartum cardiomyopathy. Circulation. 2016;133(14):1397–409.

    Article  CAS  Google Scholar 

  121. Sliwa K, Förster O, Libhaber E, Fett JD, Sundstrom JB, Hilfiker-Kleiner D, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J. 2006;27(4):441–6.

    Article  CAS  PubMed  Google Scholar 

  122. Duran N, Günes H, Duran I, Biteker M, Özkan M. Predictors of prognosis in patients with peripartum cardiomyopathy. Int J Gynecol Obstet. 2008;101(2):137–40.

    Article  Google Scholar 

  123. Fett JD, Christie LG, Carraway RD, Murphy JG. Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Clin Proc. 2005;80(12):1602–6.

    Article  PubMed  Google Scholar 

  124. Fett JD, Sannon H, Thélisma E, Sprunger T, Suresh V. Recovery from severe heart failure following peripartum cardiomyopathy. Int J Gynecol Obstet. 2009;104(2):125–7.

    Article  Google Scholar 

  125. Azibani F, Sliwa K. Peripartum cardiomyopathy: an update. Curr Heart Fail Rep. 2018;15(5):297–306.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Forster O, Hilfiker-Kleiner D, Ansari AA, Sundstrom JB, Libhaber E, Tshani W, et al. Reversal of IFN-gamma, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy. Eur J Heart Fail. 2008;10(9):861–8.

    Article  CAS  PubMed  Google Scholar 

  127. Hilfiker-Kleiner D, Haghikia A, Berliner D, Vogel-Claussen J, Schwab J, Franke A, et al. Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study. Eur Heart J. 2017;38(35):2671–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sliwa K, Blauwet L, Tibazarwa K, Libhaber E, Smedema J-P, Becker A, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study. Circulation. 2010;121(13):1465–73.

    Article  CAS  PubMed  Google Scholar 

  129. Bajou K, Herkenne S, Thijssen VL, D’Amico S, Nguyen N-Q-N, Bouché A, et al. PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat Med. 2014;20(7):741–7.

    Article  CAS  PubMed  Google Scholar 

  130. Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L, et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature. 2012;485(7398):333–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Rowe GC, Jiang A, Arany Z. PGC-1 coactivators in cardiac development and disease. Circ Res. 2010;107(7):825–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Xia G, Sun X, Zheng X, Wang J. Decreased expression of programmed death 1 on peripheral blood lymphocytes disrupts immune homeostasis in peripartum cardiomyopathy. Int J Cardiol. 2016;223:842–7.

    Article  PubMed  Google Scholar 

  133. Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, et al. Shared genetic predisposition in peripartum and dilated cardiomyopathies. N Engl J Med. 2016;374(3):233–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res. 2014;114(6):1052–68.

    Article  CAS  PubMed  Google Scholar 

  135. Ottaviani L, Sansonetti M, da Costa Martins PA. Myocardial cell-to-cell communication via microRNAs. Noncoding RNA Res. 2018;3(3):144–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kotlabova K, Doucha J, Hromadnikova I. Placental-specific microRNA in maternal circulation--identification of appropriate pregnancy-associated microRNAs with diagnostic potential. J Reprod Immunol. 2011;89(2):185–91.

    Article  CAS  PubMed  Google Scholar 

  137. Miura K, Miura S, Yamasaki K, Higashijima A, Kinoshita A, Yoshiura K, et al. Identification of pregnancy-associated microRNAs in maternal plasma. Clin Chem. 2010;56(11):1767–71.

    Article  CAS  PubMed  Google Scholar 

  138. Lamadrid-Romero M, Solís KH, Cruz-Reséndiz MS, Pérez JE, Díaz NF, Flores-Herrera H, et al. Central nervous system development-related microRNAs levels increase in the serum of gestational diabetic women during the first trimester of pregnancy. Neurosci Res. 2018;130:8–22.

    Article  CAS  PubMed  Google Scholar 

  139. Bayoumi AS, Park K-M, Wang Y, Teoh J-P, Aonuma T, Tang Y, et al. A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. J Mol Cell Cardiol. 2018;114:72–82.

    Article  CAS  PubMed  Google Scholar 

  140. Lin D, Cui B, Ma J, Ren J. MiR-183-5p protects rat hearts against myocardial ischemia/reperfusion injury through targeting VDAC1. BioFactors. 2019;n/a(n/a) Available from: [cited 2019 Nov 20].

  141. Xu L, Chen W, Ma M, Chen A, Tang C, Zhang C, et al. Microarray profiling analysis identifies the mechanism of miR-200b-3p/mRNA-CD36 affecting diabetic cardiomyopathy via peroxisome proliferator activated receptor-γ signaling pathway. J Cell Biochem. 2019;120(4):5193–206.

    Article  CAS  PubMed  Google Scholar 

  142. Feng B, Cao Y, Chen S, Chu X, Chu Y, Chakrabarti S. miR-200b mediates endothelial-to-mesenchymal transition in diabetic cardiomyopathy. Diabetes. 2016;65(3):768.

    Article  CAS  PubMed  Google Scholar 

  143. Guarino E, Delli Poggi C, Grieco GE, Cenci V, Ceccarelli E, Crisci I, et al. Circulating microRNAs as biomarkers of gestational diabetes mellitus: updates and perspectives. Int J Endocrinol. 2018;2018:6380463.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Wander PL, Boyko EJ, Hevner K, Parikh VJ, Tadesse MG, Sorensen TK, et al. Circulating early- and mid-pregnancy microRNAs and risk of gestational diabetes. Diabetes Res Clin Pract. 2017;132:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Yan M, Chen C, Gong W, Yin Z, Zhou L, Chaugai S, et al. miR-21-3p regulates cardiac hypertrophic response by targeting histone deacetylase-8. Cardiovasc Res. 2014;105(3):340–52.

    Article  PubMed  CAS  Google Scholar 

  146. Tagoma A, Alnek K, Kirss A, Uibo R, Haller-Kikkatalo K. MicroRNA profiling of second trimester maternal plasma shows upregulation of miR-195-5p in patients with gestational diabetes. Gene. 2018;672:137–42.

    Article  CAS  PubMed  Google Scholar 

  147. Zheng D, Ma J, Yu Y, Li M, Ni R, Wang G, et al. Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice. Diabetologia. 2015;58(8):1949–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Shi Y, Yan C, Li Y, Zhang Y, Zhang G, Li M, et al. Expression signature of miRNAs and the potential role of miR-195-5p in high-glucose–treated rat cardiomyocytes. J Biochem Mol Toxicol. 2020;n/a(n/a):e22423.

    Google Scholar 

  149. Zhao C, Dong J, Jiang T, Shi Z, Yu B, Zhu Y, et al. Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus. PLoS One. 2011;6(8):e23925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Arnold N, Koppula PR, Gul R, Luck C, Pulakat L. Regulation of cardiac expression of the diabetic marker microRNA miR-29. PLoS One. 2014;9(7) Available from: [cited 2019 Dec 11].

  151. Han C, Chen X, Zhuang R, Xu M, Liu S, Li Q. miR-29a promotes myocardial cell apoptosis induced by high glucose through down-regulating IGF-1. Int J Clin Exp Med. 2015;8(8):14352–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Liu X, Xiao J, Zhu H, Wei X, Platt C, Damilano F, et al. miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metab. 2015;21(4):584–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Su M, Chen Z, Wang C, Song L, Zou Y, Zhang L, et al. Cardiac-specific overexpression of miR-222 induces heart failure and inhibits autophagy in mice. CPB. 2016;39(4):1503–11.

    CAS  Google Scholar 

  154. Jia K, Shi P, Han X, Chen T, Tang H, Wang J. Diagnostic value of miR-30d-5p and miR-125b-5p in acute myocardial infarction. Mol Med Rep. 2016;14(1):184–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Slusarz A, Pulakat L. The two faces of miR-29. J Cardiovasc Med (Hagerstown). 2015;16(7):480–90.

    Article  CAS  Google Scholar 

  156. Wang Z, Wang Z, Gao L, Xiao L, Yao R, Du B, et al. miR-222 inhibits cardiac fibrosis in diabetic mice heart via regulating Wnt/β-catenin-mediated endothelium to mesenchymal transition. J Cell Physiol. n/a(n/a). Available from: [cited 2019 Nov 20].

  157. Robin V, Tim P, Javier BF, van Rick L, van Tessa H, Wouter V, et al. MicroRNA-221/222 family counteracts myocardial fibrosis in pressure overload–induced heart failure. Hypertension. 2018;71(2):280–8.

    Article  CAS  Google Scholar 

  158. Lv Y, Lu C, Ji X, Miao Z, Long W, Ding H, et al. Roles of microRNAs in preeclampsia. J Cell Physiol. 2019;234(2):1052–61.

    Article  CAS  PubMed  Google Scholar 

  159. Barchitta M, Maugeri A, Quattrocchi A, Agrifoglio O, Agodi A. The role of miRNAs as biomarkers for pregnancy outcomes: a comprehensive review. Int J Genomics. 2017;2017:8067972.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Jairajpuri DS, Malalla ZH, Mahmood N, Almawi WY. Circulating microRNA expression as predictor of preeclampsia and its severity. Gene. 2017;627:543–8.

    Article  CAS  PubMed  Google Scholar 

  161. Ura B, Feriotto G, Monasta L, Bilel S, Zweyer M, Celeghini C. Potential role of circulating microRNAs as early markers of preeclampsia. Taiwan J Obstet Gynecol. 2014;53(2):232–4.

    Article  PubMed  Google Scholar 

  162. Munaut C, Tebache L, Blacher S, Noël A, Nisolle M, Chantraine F. Dysregulated circulating miRNAs in preeclampsia. Biomed Rep. 2016;5(6):686–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhang Y, Fei M, Xue G, Zhou Q, Jia Y, Li L, et al. Elevated levels of hypoxia-inducible microRNA-210 in pre-eclampsia: new insights into molecular mechanisms for the disease. J Cell Mol Med. 2012;16(2):249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mutharasan RK, Nagpal V, Ichikawa Y, Ardehali H. microRNA-210 is upregulated in hypoxic cardiomyocytes through Akt- and p53-dependent pathways and exerts cytoprotective effects. Am J Physiol Heart Circ Physiol. 2011;301(4):H1519–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Xiao J, Pan Y, Li XH, Yang XY, Feng YL, Tan HH, et al. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4. Cell Death Dis. 2016;7(6):e2277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Arif M, Pandey R, Alam P, Jiang S, Sadayappan S, Paul A, et al. MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents. J Mol Med. 2017;95(12):1369–85.

    Article  CAS  PubMed  Google Scholar 

  167. Wang N, Chen C, Yang D, Liao Q, Luo H, Wang X, et al. Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis. Biochim Biophys Acta. 2017;1863(8):2085–92.

    Article  CAS  Google Scholar 

  168. Li H, Ge Q, Guo L, Lu Z. Maternal plasma miRNAs expression in preeclamptic pregnancies. Biomed Res Int. 2013; Available from: [cited 2019 Dec 12].

  169. Roncarati R, Anselmi CV, Losi MA, Papa L, Cavarretta E, Martins PDC, et al. Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2014;63(9):920–7.

    Article  CAS  PubMed  Google Scholar 

  170. Han W, Han Y, Liu X, Shang X. Effect of miR-29a inhibition on ventricular hypertrophy induced by pressure overload. Cell Biochem Biophys. 2015;71(2):821–6.

    Article  CAS  PubMed  Google Scholar 

  171. Li M, Wang N, Zhang J, He H-P, Gong H-Q, Zhang R, et al. MicroRNA-29a-3p attenuates ET-1-induced hypertrophic responses in H9c2 cardiomyocytes. Gene. 2016;585(1):44–50.

    Article  CAS  PubMed  Google Scholar 

  172. Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008;456:980.

    Article  CAS  PubMed  Google Scholar 

  173. Yuan J, Chen H, Ge D, Xu Y, Xu H, Yang Y, et al. Mir-21 Promotes cardiac fibrosis after myocardial infarction via targeting Smad7. Cell Physiol Biochem. 2017;42(6):2207–19.

    Article  CAS  PubMed  Google Scholar 

  174. Cheng Y, Zhu P, Yang J, Liu X, Dong S, Wang X, et al. Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4. Cardiovasc Res. 2010;87(3):431–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Yang L, Wang B, Zhou Q, Wang Y, Liu X, Liu Z, et al. MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7. Cell Death Dis. 2018;9(7):1–14.

    Article  CAS  Google Scholar 

  176. Seok HY, Chen J, Kataoka M, Huang Z-P, Ding J, Yan J, et al. Loss of MicroRNA-155 protects the heart from pathological cardiac hypertrophy. Circ Res. 2014;114(10):1585–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Heymans S, Corsten MF, Verhesen W, Carai P, van Leeuwen REW, Custers K, et al. Macrophage microRNA-155 promotes cardiac hypertrophy and failure. Circulation. 2013;128(13):1420–32.

    Article  CAS  PubMed  Google Scholar 

  178. He W, Huang H, Xie Q, Wang Z, Fan Y, Kong B, et al. MiR-155 knockout in fibroblasts improves cardiac remodeling by targeting tumor protein p53-inducible nuclear protein 1. J Cardiovasc Pharmacol Ther. 2015;21(4):423–35.

    Article  PubMed  CAS  Google Scholar 

  179. Akehurst C, Small HY, Sharafetdinova L, Forrest R, Beattie W, Brown CE, et al. Differential expression of microRNA-206 and its target genes in preeclampsia. J Hypertens. 2015;33(10):2068–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Yang Y, Del Re DP, Nakano N, Sciarretta S, Zhai P, Park J, et al. miR-206 mediates YAP-induced cardiac hypertrophy and survival. Circ Res. 2015;117(10):891–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. He Q, Wang F, Honda T, James J, Li J, Redington A. Loss of miR-144 signaling interrupts extracellular matrix remodeling after myocardial infarction leading to worsened cardiac function. Sci Rep. 2018;8(1):1–11.

    Article  CAS  Google Scholar 

  182. Li J, Cai SX, He Q, Zhang H, Friedberg D, Wang F, et al. Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction. Basic Res Cardiol. 2018;113(5):36.

    Article  PubMed  CAS  Google Scholar 

  183. Wang X, Zhu H, Zhang X, Liu Y, Chen J, Medvedovic M, et al. Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1. Cardiovasc Res. 2012;94(2):379–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Hromadnikova I, Kotlabova K, Hympanova L, Krofta L. Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood. Thromb Res. 2016;137:126–40.

    Article  CAS  PubMed  Google Scholar 

  185. Hromadnikova I, Kotlabova K, Ivankova K, Vedmetskaya Y, Krofta L. Profiling of cardiovascular and cerebrovascular disease associated microRNA expression in umbilical cord blood in gestational hypertension, preeclampsia and fetal growth restriction. Int J Cardiol. 2017;249:402–9.

    Article  PubMed  Google Scholar 

  186. Sandrim VC, Eleuterio N, Pilan E, Tanus-Santos JE, Fernandes K, Cavalli R. Plasma levels of increased miR-195-5p correlates with the sFLT-1 levels in preeclampsia. Hypertens Pregnancy. 2016;35(2):150–8.

    Article  CAS  PubMed  Google Scholar 

  187. Wang L, Qin D, Shi H, Zhang Y, Li H, Han Q. MiR-195-5p promotes cardiomyocyte hypertrophy by targeting MFN2 and FBXW7. Biomed Res Int. 2019;2019:1580982.

    PubMed  PubMed Central  Google Scholar 

  188. Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15(2):261–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Yang H-H, Chen Y, Gao C-Y, Cui Z-T, Yao J-M. Protective effects of microRNA-126 on human cardiac microvascular endothelial cells against hypoxia/reoxygenation-induced injury and inflammatory response by activating PI3K/Akt/eNOS signaling pathway. CPB. 2017;42(2):506–18.

    CAS  Google Scholar 

  190. Xiao J, Zhu X, He B, Zhang Y, Kang B, Wang Z, et al. MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II. J Biomed Sci. 2011;18(1):35.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Tijsen AJ, van der Made I, van den Hoogenhof MM, de Groot NE, Alekseev S, Wijnen WJ, et al. The microRNA-15 family inhibits the TGFβ-pathway in the heart. Cardiovasc Res. 2014;104(1):61–71.

    Article  CAS  PubMed  Google Scholar 

  192. Guan Y, Song X, Sun W, Wang Y, Liu B. Effect of hypoxia-induced microRNA-210 expression on cardiovascular disease and the underlying mechanism. Oxidative Med Cell Longev. 2019; Available from: [cited 2019 Dec 28].

  193. Duygu B, Da Costa Martins PA. miR-21: a star player in cardiac hypertrophy. Cardiovasc Res. 2015;105(3):235–7.

    Article  CAS  PubMed  Google Scholar 

  194. Khaliq OP, Murugesan S, Moodley J, Mackraj I. Differential expression of miRNAs are associated with the insulin signaling pathway in preeclampsia and gestational hypertension. Clin Exp Hypertens. 2018;40(8):744–51.

    Article  CAS  PubMed  Google Scholar 

  195. Zhu J, Yao K, Wang Q, Guo J, Shi H, Ma L, et al. Circulating miR-181a as a potential novel biomarker for diagnosis of acute myocardial infarction. Cell Physiol Biochem. 2016;40(6):1591–602.

    Article  CAS  PubMed  Google Scholar 

  196. Chen P, Pan J, Zhang X, Shi Z, Yang X. The role of microRNA-181a in myocardial fibrosis following myocardial infarction in a rat model. Med Sci Monit. 2018;24:4121–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Li A-L, Lv J-B, Gao L. MiR-181a mediates Ang II-induced myocardial hypertrophy by mediating autophagy. Eur Rev Med Pharmacol Sci. 2017;21(23):5462–70.

    PubMed  Google Scholar 

  198. Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P, et al. Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. Basic Res Cardiol. 2013;108(4):366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Stapel B, Kohlhaas M, Ricke-Hoch M, Haghikia A, Erschow S, Knuuti J, et al. Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy. Eur Heart J. 2017;38(5):349–61.

    CAS  PubMed  Google Scholar 

  200. Zhao Z, Moley KH, Gronowski AM. Diagnostic potential for miRNAs as biomarkers for pregnancy-specific diseases. Clin Biochem. 2013;46(10):953–60.

    Article  CAS  PubMed  Google Scholar 

  201. Marshall SA, Hannan NJ, Jelinic M, Nguyen TPH, Girling JE, Parry LJ. Animal models of preeclampsia: translational failings and why. Am J Phys Regul Integr Comp Phys. 2017;314(4):R499–508.

    Google Scholar 

  202. Florijn BW, Bijkerk R, van der Veer EP, van Zonneveld AJ. Gender and cardiovascular disease: are sex-biased microRNA networks a driving force behind heart failure with preserved ejection fraction in women? Cardiovasc Res. 2018;114(2):210–25.

    Article  CAS  PubMed  Google Scholar 

  203. Medzikovic L, Aryan L, Eghbali M. Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis. J Mol Med. 2019;97(10):1385–98.

    Article  CAS  PubMed  Google Scholar 

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We would like to thank Dr. Gregoire Ruffenach, Dr. Lisa Lee, and Christine Cunningham for their assistance with generating the figure.


This study is supported by the National Institutes of Health R01HL131182 (ME).

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LA and LM wrote the manuscript, SU & ME edited the manuscript. All authors gave final permission for publication. The author(s) read and approved the final manuscript.

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Correspondence to Mansoureh Eghbali.

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Aryan, L., Medzikovic, L., Umar, S. et al. Pregnancy-associated cardiac dysfunction and the regulatory role of microRNAs. Biol Sex Differ 11, 14 (2020).

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