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Pregnancy, cardiomyopathies, and genetics

J. Peter Van Tintelen, Petronella G. Pieper, Karin Y. Van Spaendonck-Zwarts, Maarten P. Van Den Berg
DOI: http://dx.doi.org/10.1093/cvr/cvu014 571-578 First published online: 22 January 2014

Abstract

Although familial forms of cardiomyopathy such as hypertrophic or dilated cardiomyopathy have been recognized for decades, it is only recently that much of the genetic basis of these inherited cardiomyopathies has been elucidated. This has provided important insights into the pathophysiological mechanisms underlying the disease phenotype. This increased knowledge and the availability of genetic testing has resulted in increasing numbers of mutation carriers who are being monitored, including many who are now of child-bearing age. Pregnancy is generally well tolerated in asymptomatic patients or mutation carriers with inherited cardiomyopathies. However, since pregnancy leads to major physiological changes in the cardiovascular system, in women with genetic cardiomyopathies or who carry a mutation pre-disposing to a genetic cardiomyopathy, pregnancy entails a risk of developing heart failure and/or arrhythmias. This deterioration of cardiac function may occur despite optimal medical treatment. Advanced left ventricular dysfunction, poor functional class (NYHA class III or IV), or prior cardiac events appear to increase the risk of maternal cardiac complications. However, there are no large series of cardiomyopathy patients who are regularly evaluated for cardiac complications during pregnancy and for certain types of inherited cardiomyopathy, only case reports on individual pregnancies are available. Pre-conception cardiologic evaluation and genetic counselling are important for every woman with a cardiomyopathy or a cardiomyopathy-related mutation who is considering having a family. In this article, we give an overview of the basic clinical aspects, genetics, and pregnancy outcome in women with different types of inherited cardiomyopathies. We also discuss the genetic aspects of pregnancy-associated cardiomyopathy, including peripartum cardiomyopathy.

  • Pregnancy
  • Cardiomyopathy
  • Heart failure
  • Genes

1. Introduction

Over the last decades, the familial character of different types of cardiomyopathies, for example hypertrophic, dilated, and arrhythmogenic cardiomyopathy (HCM, DCM, and ACM), has increasingly been recognized with the subsequent identification of genes and mutations underlying these diseases. This genetic revolution has, in turn, led to a better understanding of the pathophysiology of cardiomyopathies, which then opens up avenues for exploring potential options to influence the pathophysiological pathways and to reduce morbidity and mortality. Even though cardiomyopathies are generally inherited in an autosomal-dominant fashion, with an equal distribution of the genetic defect in both males and females, some striking sex differences in clinical presentation have been noticed.1 For example, in ACM, disease manifestations are more than two times more prevalent in males than females.2 Also in HCM and dilated cardiomyopathy (DCM), disease manifestations are more often found in males and they present at a younger age than females.3,4 This sex difference in manifestation of disease and outcome has also been shown for specific genes underlying cardiomyopathies: male carriers of a mutation in the LMNA, TMEM43, or TTN genes have worse disease outcomes compared with female carriers.57

The genetic revolution has also focused attention on the implications of pregnancy for women who have a cardiomyopathy or who carry a familial mutation pre-disposing to a cardiomyopathy. In particular, in recent years, good progress has been made in understanding the pathophysiological aspects of peripartum cardiomyopathy (PPCM), including its genetic aspects. In this review, we will briefly discuss general clinical, genetic, and pathophysiological aspects of genetic cardiomyopathies. The effects of pregnancy on women with the major different types of cardiomyopathies and cardiomyopathy developing in pregnancy and around delivery will be highlighted.

2. Cardiomyopathies and genetics

The current classification of cardiomyopathies by the European Society of Cardiology recognizes four major types of cardiomyopathies: hypertrophic, dilated, restrictive, arrhythmogenic right ventricular, and unclassified cardiomyopathies, such as non-compaction cardiomyopathy (NCCM).8 These are further subclassified according to the presence or absence of a familial or genetic component. Genetic cardiomyopathies are generally inherited in an autosomal-dominant fashion and characterized by reduced penetrance and variable expression, hampering easy identification of patients with incomplete forms of the disease, or even subclinical or pre-symptomatic forms of disease.

In the past few years, over 100 cardiomyopathy-related genes have been identified. Approximately 30 genes have been identified in HCM, 40 in DCM, 10 in RCM, 5 in ACM, and 10 in NCCM.912 These genes mainly encode proteins of the cardiac sarcomere and related structures, the cytoskeleton, the cardiac desmosome, ion channels, and the nuclear envelope. Mutations in these genes are anticipated to have a pathogenic effect on several cellular functions, such as contractile force generation and regulation, force transduction and mechanosensing, energy metabolism, calcium handling, or nuclear transcription, ultimately leading to a cardiomyopathic phenotype (reviewed by Cahill et al.13). Interestingly, there is a large overlap in the genes causing different types of cardiomyopathy (Figure 1), which may, in some instances, reflect an opposite functional effect. For example, this opposing effect has been shown in a different calcium-binding affinity of the thin filament proteins, which is increased in HCM but decreased in DCM.14

Figure 1

Representation of genes involved in different types of cardiomyopathy: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM), restrictive cardiomyopathy (RCM), and non-compaction-cardiomyopathy (NCCM). Based upon Van Spaendonck-Zwarts et al.15 and Jongbloed et al.16.

2.1 Cardiomyopathies and recurrence risk

Most genetic cardiomyopathies are autosomal dominantly inherited. This means a 50% chance for the offspring to carry the disease causing mutation. Because of age-dependent penetrance, disease usually does not manifest before adult age.17 Exceptions with foetal, paediatric, or adolescent manifestation of cardiomyopathy have been described. But this is generally believed to be due to a gene-dosage effect of multiple mutations originating from both parents who may not have overt disease themselves (yet).18,19

Mitochondrial disease is also associated with cardiomyopathies. Both mutations in nuclear and in mitochondrial DNA encoding proteins important in cellular oxidative phosphorylation underlie the associated phenotypes.20 Mitochondrial inheritance follows a matrilineal pattern of inheritance; depending on the percentage of oocytes containing mutated mitochondrial DNA, recurrence risk in offspring may be even higher than in autosomal inheritance patterns.20

3. Physiological changes in pregnancy in women and their consequences for pharmacotherapy of cardiomyopathy

Physiological changes of the cardiovascular system that occur during pregnancy are diverse.21,22 Maternal blood volume increases by 40%, matched by a comparable increase in cardiac output. The increase in cardiac output is achieved by a rise in stroke volume and, later in pregnancy, an increase in the heart rate. The increases in plasma volume and cardiac output are triggered by vasodilation, which occurs early in pregnancy due to hormonal influences, in particular relaxin.23 This hormone is part of a family of peptides that share structural similarities with insulin (two-chain molecule with disulfide bonds). It is produced by the corpus luteum in pregnancy, but also within the vasculature. Relaxin interacts with a G-protein coupled receptor, LGR7 (or RXFP1), which is located in the vasculature and the heart among other tissues. Activation of LGFR7 leads to activation of mitogen-activated protein kinase and phosphoinositide-3 kinase in target cells. Relaxin thus modulates nitric oxide production and the endothelin system (activation of endothelin type B receptor), leading to systemic and renal vasodilation. In addition, relaxin has anti-fibrotic properties by modulating matrix-metalloproteinase activity, which also affords in increase in vascular compliance. Remodelling of placental vessels in the second trimester results in a further decrease in systemic vascular resistance accompanied by a lowering of the blood pressure. The above circulatory changes are matched by a 10–20% increase in the left ventricular mass. An important signalling pathway involved in this physiological hypertrophic response includes activation of calcineurin by a rise in calcium early in pregnancy.24 Activated calcineurin dephosphorylates cytoplasmic nuclear factor of activated T cells (NFAT), inducing translocation of NFAT to the nucleus of the cardiomyocytes, which in turn causes activation of pro-hypertrophic genes. Of note, progesterone also plays a role in this pathway by increasing calcineurin levels. Progesterone and oestrogen levels also increase during pregnancy and are known to influence the cardiovascular system.22 This, together with substantial metabolic changes that occur during pregnancy and post-partum, is further discussed elsewhere in this issue.25,26

A rise in several blood coagulation factors and a decrease in fibrinolytic activity result in a hypercoagulable state. During labour, stroke volume is increased because of anxiety, pain, and an increased venous return, resulting from the uterine contractions. Finally, after delivery, there is an increase in cardiac output depending on blood loss during labour, auto-transfusion directly after delivery as a result of uterus contraction, and decompression of the inferior caval vein and resorption of oedema. All these cardiovascular changes during pregnancy and delivery may exert a burden on the heart and, in the case of genetic or other types of cardiomyopathy, various problems may ensue, namely heart failure, arrhythmias, and thrombo-embolic events. Moreover, these changes, combined with metabolic changes during pregnancy, influence pharmacokinetics and require the medication dosage to be adjusted. Drug absorption is usually decreased and renal elimination increased, thus decreasing the total plasma concentration of the drug. The expansion of the blood volume leads to a dilution and decrease in blood proteins, causing higher concentrations of unbound drugs in the blood. Furthermore, hepatic metabolization may increase or decrease.27,28

4. Pregnancy in women with established genetic cardiomyopathy

Many of the potential pregnancy-related problems in women with an established cardiomyopathy, including the subset of women with genetic cardiomyopathy, are related to the physiological changes of the cardiovascular system that occur during pregnancy like mentioned above.21,22 In this section on pregnancy in women with an established cardiomyopathy, we will give a brief overview of relevant issues that ideally have to be discussed before a pregnancy takes place and give an overview of the effects of pregnancy on different major forms of cardiomyopathy.

4.1 Counselling and risk stratification in women with a genetic cardiomyopathy before pregnancy

In patients with a genetic cardiomyopathy, the following issues should be considered, ideally before pregnancy: the specific underlying cardiomyopathy and its severity [including the New York Heart Association (NYHA) functional class and left ventricular systolic and diastolic function], effects of pregnancy on the disease, effects of the disease or necessary medication on the unborn child, medication regime during pregnancy, the possibility of further palliative or corrective procedures, implantable cardioverter defibrillator implantation, maternal life expectancy and ability to care for a child, and the risk of heart disease in the offspring.2931 These issues should be discussed with the woman or couple, and a plan for pregnancy management should be made, scheduling outpatient clinic visits at least once every trimester and more often in the case of serious disease. In addition, effective and safe contraception should be discussed with all sexually active girls and women with cardiomyopathy.30 Issues related to specific types of cardiomyopathies will be discussed below.

4.2 Pregnancy in women with HCM

Hypertrophic cardiomyopathy (HCM) is defined by increased left ventricular wall thickness that cannot be explained by abnormal loading conditions such as hypertension or valvular disease.8 In this revised definition, morphology rather than aetiology determines the diagnosis. Diseases such as amyloidosis fall in this classification as part of the differential diagnosis of HCM. However, in adolescents and adults, and in pregnant women, HCM is mainly caused by mutations in sarcomeric cardiac protein genes, e.g. MYBPC3, MYH7, TPM1, TNNT2, and TNNI3 (Figure 1). The estimated prevalence of HCM is 1:500. Familial disease is present in the majority of cases, mainly with autosomal-dominant inheritance. Phenotypic expression is variable. The disease may become manifest at any age and the clinical severity may vary from asymptomatic to severe (often diastolic) heart failure, left ventricular outflow tract obstruction, mitral valve dysfunction, arrhythmias, or even sudden cardiac death. Many women with HCM tolerate pregnancy well, but a complicated course of pregnancy has been reported in women with severe disease (Table 1).32,33 Maternal mortality is low and has only been described in patients with a very high risk due to severe hypertrophy, high gradient, or a family history of malignant arrhythmias.34 The left ventricular outflow tract gradient is influenced in opposite ways as a result of the volume load of pregnancy: the ventricular dilatation reduces the gradient, but the increased stroke volume will increase the gradient—the net effect is a modest increase.32 As in all women with heart disease and previous arrhythmias, arrhythmias tend to recur during pregnancy,29,35 but pregnancy itself does not seem to cause arrhythmias in patients without a history of arrhythmias.34 Worsening of symptoms such as dyspnoea and chest pain mainly occurs in women who were symptomatic before pregnancy.34,36 So, it seems that the risk of maternal complications during pregnancy is mainly determined by pre-pregnancy functional class, pre-pregnancy arrhythmias, and possibly also by the severity of LV outflow tract obstruction and family history. These items can be used to guide the risk assessment and management of the pregnancy according to the ESC guidelines for cardiomyopathies in pregnancies.30 Women with a low risk (modified WHO risk class II) should be followed clinically and echocardiographically each trimester, with additional 24 h electrocardiography when needed. Women with a high risk of complications (modified WHO risk class III) should be followed more frequently, every 4–8 weeks.30 HCM rarely represents a contra-indication for pregnancy. Women who use beta-blockers before pregnancy should continue these during pregnancy. When women become symptomatic during pregnancy, a beta-blocker needs to be started. Alternatively, verapamil is an option, but caution is advised because there is risk of an atrioventricular block in the foetus. For arrhythmia treatment, beta-blockers or sotalol is favoured over amiodarone, which should only be given for life-threatening arrhythmias that do not respond to other therapy. It can be concluded that pregnancy in HCM is generally well tolerated, but complications can be anticipated in women with severe pre-pregnancy disease.

View this table:
Table 1

Genetic cardiomyopathies and pregnancy outcomes

Pregnancy outcomeRemarks/expert opinion
DCMAsymptomatic or mild symptomsLow risk of adverse events38,40Predictors adverse events: moderate-severe LV dysfunction and/or NYHA class III/IV40,42
First diagnosed during pregnancy (first trimester)Relatively poor
Severe LV dysfunctionPoor
HCMNo or only mild symptoms before pregnancyIn general: goodPredictors maternal morbidity: poor NYHA functional class34
Moderate-severe symptoms before pregnancy10–30% worsenIn particular when LVOT obstruction is present32,34
Severe obstruction (gradient >100 mmHg)Highest risk of deterioration
RCMNo data availableSymptomatic patients are advised not to get pregnant31
NCCMHighly variable: from severe arrhythmias/LVAD therapy to no symptomsOnly a limited numbers of cases described. Asymptomatic: good prognosis; NYHA II/IV, sustained ventricular arrhythmias, enlarged left atrium: unfavourable outcome
ARVCBelieved to be goodOnly based on small series and case reports
Advise not to get pregnant in patients with ventricular arrhythmias or RV failure31
PPCM20–25% end-stage heart failureHigh recurrence in subsequent pregnancies, in particular when LV function is reduced

4.3 Pregnancy in women with DCM

DCM is characterized by dilation and impaired contraction, primarily of the left ventricle (LV). Many causes for DCM have been identified, including ischaemic heart disease, hypertension, infectious diseases (viral myocarditis), alcohol abuse, and medication toxicity. The estimated prevalence of DCM is 1:2500. In ∼50% of the cases of DCM, no causal mechanism can be discovered (idiopathic DCM), whereas familial disease is present in ∼35% of patients with idiopathic DCM, mainly with autosomal-dominant inheritance. Genes involved in DCM mainly encode proteins of the nuclear envelope (LMNA) and the cardiac sarcomere and its related structures (like TTN; Figure 1).10 DCM leads to progressive heart failure, sometimes necessitating heart transplantation. Other problems are thrombo-embolism, arrhythmias, and sudden cardiac death. Only a few studies on the pregnancy outcomes of women with idiopathic DCM have been published.33,3742 No studies are available on genetic DCM and pregnancy, but outcome is probably comparable in genetic vs. non-genetic DCM. Patients should be classified, stratified, and treated according to the guidelines for pregnancies in cardiomyopathies:30 pregnancy in asymptomatic or mildly symptomatic DCM patients seems to be associated with a low risk of adverse maternal events. Predictors of such adverse events are moderate or severe left ventricular dysfunction and/or NYHA functional class III or IV. Foetal complication rate is also increased, depending on the presence of maternal and obstetric risk factors. In comparison with non-pregnant women with DCM, pregnant women with DCM experience more adverse events. This can probably be explained by the increased haemodynamic challenge in pregnant patients and by the fact that medical treatment in pregnant patients is problematic. In particular, the use of ACE inhibitors is prohibited because of their teratogenic and fetotoxic effects. Of note, when DCM is first diagnosed during pregnancy (in the first trimester), outcome appears to be relatively poor.37,42

Blatt et al.37 have investigated the value of BNP in pregnant women with DCM. Although their sample size was rather small, outcome in the women with an elevated NT-proBNP level prior to pregnancy (>300 pg/mL) was complicated in the perinatal period (acute heart failure, pulmonary embolism), whereas outcome was uncomplicated in the women with low BNP values.37 In women without cardiac disease, BNP levels do not rise during pregnancy, although they may increase in the setting of pre-eclampsia or eclampsia. In contrast, in women with congenital heart disease (structural defects), NT-proBNP levels are elevated compared with healthy pregnant women, and are associated with impaired utero-placental flow and subsequent poor offspring outcome.43 In pregnant women with heart disease (including cardiomyopathy), BNP levels are associated with adverse maternal cardiac outcome, and have a high negative predictive value.44

It can be concluded that due to increased haemodynamic challenge in pregnant women with DCM adverse events can be anticipated in particular in those with moderate-severe left ventricular dysfunction and/or NYHA functional class III or IV. Medical treatment is a challenge in those patients.

4.4 Pregnancy in women with NCCM

NCCM is an increasingly recognized, morphologically distinct, cardiomyopathy. It usually affects the LV and is characterized by thickened myocardium composed of two layers: a thin compacted epicardial layer (C) and a thicker non-compacted endocardial layer (N) with an N/C ratio >2, and with deep intertrabecular recesses that are perfused with the blood from the left ventricular cavity, as shown by colour Doppler (Figure 2).45,46 Cardiac MRI can be of an additional value to confirm the diagnosis and prevent overdiagnosis.47 In a position paper from the European Society of Cardiology, it is stated that NCCM may be either a separate cardiomyopathy or a morphological trait shared by phenotypically distinct cardiomyopathies,8 it was therefore assigned to the ‘unclassified cardiomyopathies’ group. The disease can present at any age, from the foetal to the elderly. There is a slight male pre-dominance. Familial occurrence is described in 20–50% of cases, whereas sporadic cases also occur.47 Genes described to be associated with NCCM include TAZ (especially in children), and genes encoding sarcomeric proteins such as MYBPC3 and MYH7 (Figure 1).47,48 There is genetic heterogeneity and no specific genotype–phenotype association has been identified so far. NCCM can be associated with several congenital syndromes and structural congenital heart defects, and association with neuromuscular disorders has also been reported.

Figure 2

Apical four-chamber echocardiographic images of a patient with left ventricular non-compaction cardiomyopathy. Two-dimensional image showing non-compacted areas in the apex and lateral wall (left panel). Measurement of non-compacted vs. compacted wall thickness (middle panel). Colour Doppler perfusion of intertrabecular recesses (right panel). LV, left ventricle; RV, right ventricle; LA, left atrium; RA, right atrium.

The clinical presentation of NCCM varies widely, depending on the presence of associated congenital disease, age, and whether the disease is diagnosed by family screening. Patients may be asymptomatic but in more advanced cases heart failure, arrhythmias, and thrombo-embolic events characterize the disease. Screening of first-degree family members is advised.49

The volume load of pregnancy may precipitate heart failure in some previously asymptomatic women. In some of these women presentation in late pregnancy or shortly after delivery has been described and PPCM was diagnosed.48,5052 Because no echocardiographic data from before pregnancy are available in these cases, it remains uncertain whether they represent true PPCM cases. Pregnancy has rarely been described in women with NCCM: 11 cases have been reported in the literature.31,5052 Arrhythmias and/or severe heart failure, even necessitating implanting a left ventricular assist device or transplantation, were observed in some of these women, whereas others did well. Data on pregnancy in NCCM are so scarce that specific advice for treatment cannot be given and is only based on expert opinion. Heart failure treatment should follow guidelines with appropriate adjustment to protect the foetus from adverse medication effects.30 There is no evidence to justify routine anticoagulation therapy in pregnant women with NCCM. The pregnancies described in the literature were not complicated by thrombo-embolic events. As in other cardiomyopathies, in pregnant NCCM patients with atrial fibrillation or with impaired LV function (LVEF <40%), anticoagulation should be given (low-molecular-weight heparin or warfarin, according to the stage of pregnancy).30,47 Research in pregnancy and NCCM may remain limited to collecting data from pregnancies in affected mothers. Initiatives such as ROPAC (Registry On Pregnancy and Cardiac Disease) should eventually contribute to a better understanding of the clinical outcome in these pregnancies.53,54 Until that moment, because only limited data on pregnancy in women with NCCM are available, treatment is mainly based on expert opinion.

4.5 Pregnancy in women with ARVC

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is clinically characterized by ventricular arrhythmias, generally occurring between the second and fourth decade of life, and structural and functional abnormalities of the right ventricle (RV). Nowadays left ventricular abnormalities are increasingly being recognized. Therefore, the disorder is also referred to as arrhythmogenic cardiomyopathy (ACM), of which sudden cardiac death is an important feature. Fibrofatty replacement of cardiomyocytes in the RV, LV, or both, is considered pathognomonic for the disease. It is an autosomal dominantly inherited disease with age-dependent penetrance and variable expressivity. Clinically, there is a male pre-dominance in disease manifestation.55

In up to 50% of cases, mutations in genes encoding proteins of the cardiac desmosome are being identified, in particular truncating mutations in plakophilin 2 (PKP2) (Figure 1).56 In addition, mutations in other non-desmosmal genes such as TMEM43, TTN, LMNA, DES, PLN, and CTNNA3 have been identified11 (Figure 1).

The exact pathophysiological mechanism underlying ACM has not yet been fully elucidated. In addition to mechanical effects of a defective desmosome, regulation of gene expression may be influenced by potential intracellular signalling pathways that mediate desmosome–nucleus cross-talk. Plakoglobin is believed to transfer to the nucleus, leading to inhibition of the canonical Wnt-catenin β1 signalling with subsequent stimulation of adipogenesis and proliferation of adipocytes.57 In ACM, diminished expression of gap junction proteins and a decreased number and size of gap junctions is thought to lead to electrical uncoupling with conduction slowing, and thereby pre-dispose the heart to electrical instability.58 The cardiac sodium-channel protein type 5 subunit α (Na(V)1.5) also co-exists with plakophilin-2 in the same molecular complex, leading to disturbed sodium channel current and a disturbed propagation velocity of action potentials.59

Recently, regular sports activity has been identified as a risk factor for the development of clinical manifestations in mutation carriers and as a risk factor for ventricular arrhythmias in ARVC mutation carriers.60 From these data, one might surmize that pregnancy could be a risk factor for developing ARVC or its disease manifestations in pregnant mutation carriers. Yet there are no data to suggest that pregnancy is a risk factor or that multiple pregnancies lead to earlier or more severe disease in women with ARVC mutations. Indeed, from the current literature, it appears that pregnancy is generally well tolerated in woman with ARVC. However, this observation is mainly based on a series of anecdotal case reports and small published series.2,61

ARVC is diagnosed more frequently in males than in females. In addition to a putative difference in physical activity level, hormonal differences have been proposed as a cause. The hormonal differences may be an explanation for the favourable pregnancy outcome in woman with ARVC. Interestingly, the role of sex hormones in the development of cardiomyopathy has been incorporated in a model of a Lamin A/C (LMNA)-related cardiomyopathy. Neonatal rat cardiomyocytes expressing mutant LMNA constructs and LmnaH222P/H222P mice demonstrated a nuclear accumulation of an androgen receptor and its co-activators. Experiments in LmnaH222P/H222P mice (castrated males and ovariectomized females), including treatment with testosterone or an androgen receptor antagonist, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling.62

In conclusion, from the literature it seems that pregnancy in women with ARVC is generally well tolerated.

4.6 Pregnancy in women with RCM

Restrictive cardiomyopathy is characterized by an impaired ventricular filling with restrictive physiology and normal or near-normal systolic function, and is generally believed to have a poor prognosis.63 Genes involved in inherited RCM mainly encode proteins of the cardiac sarcomere (Figure 1). There are no data available on pregnancy in RCM patients. This is probably because RCM is quite rare and the clinical course in RCM is often severe with a poor prognosis. In asymptomatic cases, an uneventful pregnancy may be anticipated, but expert opinion advises symptomatic patients with RCM not to become pregnant.31

5. Cardiomyopathies developing during pregnancy or in the peripartum phase: introduction

Cardiomyopathy may first become overt during pregnancy or after delivery. This may either be the result of unmasking of a subclinical or pre-symptomatic cardiomyopathy (see specific sections on different cardiomyopathies) or may be due to specific pregnancy-related forms of cardiomyopathies that develop during pregnancy or in the peripartum phase.

5.1 Cardiomyopathy developing in pregnant women: genetic cardiomyopathy unmasked by pregnancy

In pregnant women, cardiomyopathy may also develop before the last gestational month which is referred to as pregnancy-associated cardiomyopathy (PACM).64 Recently, it has become apparent that both PPCM and PACM can be an initial manifestation of familial DCM (see next section for PPCM).6567 In their genetic study, Morales et al.66 included PACM, in addition to PPCM cases. They determined familial clustering of DCM in 23 (55%) of 42 unrelated cases with PPCM/PACM. Mutations in cardiomyopathy-related genes were found in 6 of 19 cases with genetic data available, each in a different gene, and with variable evidence of pathogenicity.66

5.2 Cardiomyopathy developing in pregnant women: PPCM

According to a recent statement from the Peripartum Cardiomyopathy Working Group of the ESC, PPCM is defined as an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the first month following delivery, in the absence of other causes of heart failure.68 Its clinical outcome is highly variable, ranging from full recovery to rapid progression to end-stage heart failure. It is a rare condition in Western countries (probably in the range of 1 : 3000 pregnancies), yet in specific regions such as Haiti and Nigeria, it is far more prevalent and may occur in up to 1 in 300 pregnancies.69,70 The variable outcomes and regional differences suggest a variety of underlying mechanisms and, indeed, several risk factors and possible underlying pathological processes in PPCM have been proposed. Inflammation, abnormal autoimmune responses, apoptosis, angiogenic imbalance, and genetic factors are believed to play a role in pathogenesis, but the exact mechanisms are not yet fully known.69 Recently, involvement of a cascade with oxidative stress, the prolactin-cleaving protease cathepsin D, and the nursing hormone prolactin, was proposed, opening avenues for a disease-specific therapy, i.e. blockage of prolactin by bromocriptine.71,72 Angiogenic imbalance may explain why PPCM develops in late pregnancy, and why pre-eclampsia and multiple pregnancies are important risk factors.73 Up to 20–25% of women with PPCM develop end-stage heart failure, while one-third to a half show recovery to normal left ventricular function. When reduced LV function persists, but also after full recovery of PPCM, there is an increased risk of mortality and of developing heart failure in subsequent pregnancies.68,70 If the LV function has not recovered to normal, any subsequent pregnancies should be carefully considered and the substantial risks should be discussed with the patient.

5.2.1 Genetics and PPCM

A positive family history for cardiomyopathy may point to a genetic cause.65,66,74 Anecdotal cases of familial occurrences of PPCM and DCM, as well as familial clustering of PPCM, have been reported.7582 Recently, it has become apparent that PPCM can be an initial manifestation of familial DCM.6567 We identified PPCM patients in a substantial number of DCM families (5/90, 6%); PPCM occurred in two members in one of these families. In a reverse approach, cardiologic screening of first-degree relatives of three PPCM patients who did not show full recovery revealed undiagnosed DCM in all three families. Finally, genetic analyses revealed a mutation in TNNC1 segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case.65

Ntusi et al.67 reported a case series from Africa with two of 29 patients (7%) with familial DCM with at least one relative with PPCM. Accordingly, Haghikia et al.74 recently reported a positive family history of cardiomyopathy in 16.5% (19/115) of PPCM cases in a German PPCM cohort, supporting the idea that genetic factors may be involved in some PPCM patients.

These findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. Cardiologic screening for covert DCM in first-degree relatives of PPCM patients is therefore advisable. Besides, cardiologic screening during pregnancy and puerperium should be considered for first-degree relatives (or relatives carrying an underlying mutation) of familial DCM patients.

There may also be genetic factors specific for PPCM development. Horne et al.83 performed a small genome-wide association study and reported a locus near the PTHLH gene. Given the fact that mice with cardiomyocyte-specific deletion of STAT3 develop PPCM, the STAT3 gene might also be involved in human PPCM, but there is no human genetic data supporting this yet.71 Genetic variation might be responsible, to some extent, for the large variation in incidence seen between geographic regions, especially for the hotspots.69,70

5.3 Mouse models for PPCM

Only a limited number of PPCM mouse models have been described so far. In addition to the aforementioned STAT3 deletion mouse model, G protein q (Gαq) PGC1α and mice with a combined deficiency of dystrophin and beta1-integrin have been described.73,84,85

Transgenic mice with cardiac-restricted overexpression of the α-subunit of Gαq) exhibit a lethal, PPCM accompanied by apoptosis with a peak incidence of heart failure within 1 week after delivery.84 Interestingly, these mice also demonstrate a lower survival rate with increasing numbers of pregnancies. Reduction in cardiac myocyte apoptosis by caspase inhibition improved left ventricular function and survival indicating that cardiac myocyte apoptosis plays a causal role in the pathogenesis of cardiomyopathy in this model.85 Mice lacking cardiac PGC-1α, a powerful regulator of angiogenesis, also develop profound PPCM. In this knock-out mouse model, the PPCM is entirely rescued by pro-angiogenic therapies.73 Finally, mice with a cardiomyocyte-specific deletion of beta1-integrin crossed in a Duchenne muscular dystrophy background, lacking dystrophin, show a high mortality in peri- and post-partum by 6 months of age, with severe myocardial necrosis, fibrosis, and extensive dystrophic calcification.86

Because female transgenic mice are not always followed up after pregnancy, it cannot be excluded that PPCM also develops in other transgenic animals models. It would be of scientific importance to also evaluate these mice during and after pregnancy and we encourage basic science groups to do so.

6. Summary and conclusions

The physiological changes of the cardiovascular system during pregnancy—an increase in blood volume, cardiac output, stroke volume, and heart rate—are believed to accelerate disease manifestations in women with an inherited cardiomyopathy or even those carrying a cardiomyopathy-related mutation. In asymptomatic patients, pregnancy is generally well tolerated. Maternal complications may, however, be anticipated in the presence of a poor functional NYHA class (III/IV), severe left ventricular dysfunction, left ventricular outflow tract obstruction, or when prior cardiac events have occurred. Because only limited data, often from small series or case reports, are available on pregnancy in patients with an inherited cardiomyopathy clinicians have to rely on expert opinions when they evaluate pregnancies in cardiomyopathy patients. Because the clinical status before pregnancy is an important predictor for outcome, we recommend timely consultation when patients are contemplating pregnancy.

Acknowledgements

Jackie Senior is thanked for editing this manuscript.

Conflict of interest: none declared.

Footnotes

  • This article is part of the Review Focus on Pregnancy-mediated Heart and Vascular Disease.

References

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