As soon as the baby is delivered, and the patient is hemodynamically stable, standard therapy for HF can be applied. Due to high metabolic demand and fluid intake during nursing it may be considered to stop lactation and breast feeding in PPCM patients with severe illness, after weighing all arguments in favor of breast feeding. As outlined below, bromocriptine is recommended for ablactation because of potential beneficial side effects on PPCM [13, 17]. In patients with PPCM, a subsequent pregnancy carries a recurrence risk of 30–50% [10, 18]. When ejection fraction has not normalized a subsequent pregnancy should be discouraged. Even if ejection fraction is restored to normal, there is still a need for counseling for recurrence risk.
Table (s) with treatment guidelines
Therapy/disease manifestation | ACEI, ARB, ß-blockers | Diuretics | Digitalis, levosimendan, nitrates, hydralazine | Others |
|---|---|---|---|---|
Manifestation before partum | Delete ACEI, ARB | Possible, use with caution | Possible | LMW heparins and coumarins may be considered for anticoagulation |
After partum | Delete ACEI, ARB, if breast feeding is planned | Possible | Possible | As above |
Severe Heart failure | See above | Possible | Possible | Consider transfer to specialized center, discuss mechanical support |
Dilated Cardiomyopathy
Introduction
Cardiomyopathies (CM) represent rare, but severe causes of HF. Most genetic CM are due to autosomal gene variations and are therefore expected to occur with the same prevalence in women and men. However, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), and probably also non-compaction and arrhythmogenic right ventricular CM have a greater prevalence in men than in women [19–21]. It has been hypothesized that women are better protected against ventricular dilatation and systolic dysfunction than men or, compensation for the genetic defect in these syndromes appears to be more efficient in women. Therefore, genetic defects lead more rarely to manifest disease in women than in men [22].
Clinical Problem and Pathophysiology
Dilated cardiomyopathies manifest as acute or chronic HF. Pathophysiology is based on functional and morphological alterations of the left and or right ventricle and the response of the periphery. Sex-specific adaptation of the heart will lead to more dilated eccentric ventricles in men and smaller, more hypertrophic ventricles in women [22] (Fig. 8.1). However, this has not yet been fully analyzed in the human and no sex-specific normal values exist. Metabolic switches also differ among women and men. Men exhibit a stronger downregulation of fatty acid oxidation [23]. In animal models, significant sex differences are found for different types of CM induced by different genetic lesions. In most of the genetic CM models, male mice appear more sensitive to genetic interventions than females, and exhibit higher mortality, more severe hypertrophy and more functional impairment. Some of these models mimic human CM. In some models, the severe phenotype in the males could be prevented by estrogen administration [24]. A number of disease genes, most of them affecting cytoskeletal and sarcomere composition, for DCM have been identified, without difference between women and men [2]. A number of cases remains unexplained so far. Diagnosis of genetic components is particularly important, when younger women and men with a desire for children are affected. Specialists for genetic counseling should be involved in management of these patients.
Fig. 8.1
Different mechanisms of myocardial adaptation in the male and in the female human heart. Adapted from European Heart Journal, Regitz-Zagrosek 2016 [26]
Dilated cardiomyopathy may occur in pregnancy. The clinical manifestation and diagnostic criteria resemble the non-pregnant disease manifestation. They differ from PPCM by the time of manifestation. DCM is often unmasked during the first or second trimester when the hemodynamic load is increasing. Preexisting DCM may exhibit marked deterioration during pregnancy [4]. Patients with LVEF <40%, a predictor of high pregnancy risk, should be monitored in a tertiary care centre. Worsening of DCM during pregnancy may occur and in patients with very severe disease, abortion should be discussed.
Diagnostic Pathway
Diagnosis is based on the clinical signs and symptoms of heart failure—dyspnea, fatigue and exercise intolerance—and alterations of ventricular morphology and function after exclusion of a specific cause for HF. No sex-specific guidelines exist. First diagnosis is usually made by echocardiography, according to the guidelines. Volumes are enlarged, ventricular walls are thin, systolic function and in most cases also diastolic function is decreased. Ventricular, atrial and vascular diameters should be normalized to body surface area to correct for different body sizes in women and men. Coronary angiography and myocardial biopsy may be needed to exclude specific causes of HF, such as coronary, valvular or inflammatory disease. In the ECG, a number of different arrhythmias may be visible. Heart rate-corrected QTc intervals are usually longer in women than in men, putting them into greater danger for ventricular arrhythmias. Atrial fibrillation is a more frequent event in men, but has a greater negative impact on the prognosis in women [25].
The most important biomarker is NT-BNP. Its increase is associated with adverse prognosis. Some studies have claimed that sex-specific normal values should be considered, but this has not been convincingly worked out. High-sensitive Troponin is emerging as a novel biomarker and it appears that women have lower normal values than men [26]. Its sex-specific predictive value in DCM has not yet been clarified.
Treatment
Medical Therapy
Standard therapy for HF is used for treatment of DCM. Even though some sex differences are described for the effects and adverse effects of medical therapy this has not yet let to sex-specific recommendations in the guidelines. Mortality under digitalis treatment was higher in women than in men in a post-hoc analysis of the largest randomized prospective trial on digitalis in HF [27]. Women with HF also have a higher rate of adverse drug events than men especially with diuretics, anticoagulants, digoxin and ACEI [26]. Since DCM may occur in pregnancy, specific problems arise when pregnant women are concerned. In this case, ACEI and ARB must be withdrawn, Diuretics and antithrombotic drugs must be used with more caution, as described above for PPCM.
Cardiac Resynchronization Therapy (CRT)
Resynchronization therapy is an emerging new option for treatment of DCM and HF. So far, women are poorly represented in clinical trials for cardiac resynchronization therapy (CRT) [28–30]. Surprisingly, women experienced more benefit from CRT than men [30, 31] and even earlier indications for its use in women have been discussed. In a recent FDA meta-analysis, three major clinical trials with mild HF suggested an indication for CRT in women with a shorter QRS-duration than in men [32].
Ventricular Assist Device (VAD)
There are no sex differences in the recommendations. However, just based on body size, less women qualified for device therapy in recent years. A severe survival deficit in women after device implantation was identified by registry analysis of the international society of heart and lung transplantation (ISHLT). This is now being changed with miniaturization of the devices. If women and men were compared independent of the device type and clinical state at presentation is taken into account survival benefit for both genders seems to be similar [33]. Referral of women in more severe disease state in earlier studies may explain some of the survival disadvantages described.
Heart Transplantation
More men than women undergo the demanding procedure of heart transplantation. Women are more frequently donors whereas men are more frequently recipients. In a large cohort of patients with idiopathic DCM at the German Heart Institute less than 20% were women, suggesting a referral bias against women. Women referred for transplantation were more frequently in NYHA III-IV than men, had lower exercise tolerance, respiratory efficiency and kidney function. Women referred for transplantation also had a significantly lower incidence of diabetes than men, notwithstanding the same prevalence of diabetes in women and men with heart failure. We conclude that women are referred at a more advanced disease state and relative contraindications such as diabetes are taken more seriously in women [25]. An international multicenter prospective study on referral for heart transplantation, organ allocation and survival appears mandatory. See Fig. 8.2.
Fig. 8.2
Donor recipient relation in heart transplantation. Women are more frequently donors, men are more frequently recipients. Adapted from European Heart Journal, Regitz-Zagrosek 2016 [26]
Outcomes
In general, women have better clinical outcomes than men, even though they have poorer quality of life [34]. In most cases of DCM, women appear to survive better than men. Thus it has been suggested that women have more efficient compensatory mechanisms to compensate stress. Less profibrotic changes in the heart and a better metabolic adaptation may play a role there [19, 20]. These observations may pave the way for new therapeutic developments [35, 36].
Hypertrophic Cardiomyopathy
Introduction
Hypertrophic cardiomyopathy (HCM), and probably also non-compaction and arrhythmogenic right ventricular CM have a greater prevalence in men than in women [19–21]. This is astonishing, since they are transmitted by autosomal variants that occur with the same frequency in women and men [26]. As in DCM, it has been hypothesized that women are better protected against fibrosis and ventricular dysfunction than men or, compensation for the genetic defect in these syndromes appears to be more efficient in women [22]. Sex specific survival patterns have not yet been broken down to specific HCM mutations, which are detected in increasing numbers. Phenotypes also depend on genotypes. In a case with a TNI mutation, transition of HCM to DCM has been described in a young woman [37].
Clinical Problem, Manifestation in Pregnancy
Severe problems in HCM arise from the fact that they most often manifest in young adults. In men, they often cause sudden death in active sportsmen and it is not clear why this is not the case in women. Clinical features of HCM are frequently more severe in men than in women, if with the same genetic variant. We described a family where the mother, apparently clinically unsuspicious and undiagnosed transmitted the assumed disease gene, a variant in the MYBPC3, to three sons that underwent heart transplantation or pacemaker implantation at young age (Fig. 8.3). Genetic diagnosis is the same for women and men. Diagnosis of genetic components is particularly important, when younger women with a desire for children are affected. An experienced counselor should be involved in these cases.
