Current Management of Patients with Severe Acute Peripartum Cardiomyopathy: Practical Guidance from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy

Acute heart failure (AHF) due to peripartum cardiomyopathy (PPCM) provides a challenge for treating physicians. Moreover, in patients still pregnant, therapeutic interventions need always to consider the health of both the mother and the foetus. Especially challenging are severe forms of PPCM, as the mortality of these women is quite high. The use of inotropic drugs and mechanical circulatory support devices may be necessary in the initial phase of severe forms of acute PPCM. Many patients, after initial stabilization, recover LV function.1-3 Unfortunately, some patients need further mechanical circulatory support or urgent heart transplantation despite maximal therapy. In addition, the time frame and extent of recovery are unpredictable, and patients may suffer from cardiac arrest due to ventricular fibrillation in the first months after diagnosis.4 The clinical course may be further aggravated by atrial and/or ventricular thrombus formation with subsequent cardio-embolic complications. As evidence-based data from randomized clinical trials are scarce, in this practical guidance we summarize recent data and clinical experience in the treatment of patients with severe acute PPCM to help physicians in the diagnosis, acute treatment, and long-term management of these young critically ill patients. The Working Group on PPCM of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) recently proposed a new simplified definition of PPCM as an idiopathic cardiomyopathy frequently presenting with heart failure secondary to LV systolic dysfunction (LVEF <45%) towards the end of pregnancy or in the months following delivery, if no other cause of heart failure is found.1 Since no specific test to confirm PPCM exists, it remains a diagnosis of exclusion. In particular, aggravation of pre-existing heart disease by pregnancy-mediated haemodynamic changes should be differentiated from PPCM. The pathophysiology of PPCM remains poorly understood. The current status of knowledge of the pathophysiological mechanisms of PPCM has been published elsewhere.3 A ‘two-hit’ model of angiogenic imbalance in the heart during the peripartal period has recently been proposed, combining systemic antiangiogenic signals during late pregnancy and host susceptibility through insufficient local proangiogenic defences in the heart.1-3, 5 Angiogenic imbalance can further be triggered by oxidative stress activating cathepsin D, a protease responsible for the cleavage of the nursing hormone prolactin into the angiostatic and proapoptotic 16 kDa subfragment.4, 6 Most patients admitted with PPCM present typical symptoms of AHF associated with signs of congestion. Because early signs and symptoms of heart failure in PPCM patients may mimic physiological changes occurring during/after pregnancy, delayed diagnosis may occur. The differential diagnosis of acute PPCM includes myocarditis, pre-existing cardiomyopathy, valve disease, or congenital heart disease. In the case of cardiogenic shock, pregnancy-associated myocardial infarction, pulmonary embolism, and amniotic liquid embolism should be immediately ruled out to provide adequate care (Table 1). Earlier onset (during second trimester) Sometimes family history Consider MRI Consider genetic test MRI Consider myocardial biopsy As for any AHF, initial evaluation of patients with suspected acute PPCM includes two parts, which should be performed simultaneously to allow timely diagnosis and treatment delivery: evaluation of cardiopulmonary distress; and confirmation of the diagnosis with additional tests. Evaluation of cardiopulmonary distress is crucial because it will influence subsequent treatment and patients' allocation. The presence of criteria defining cardiopulmonary distress should lead to intensive cardiac care unit admission: haemodynamic instability (systolic blood pressure <90 mmHg, heart rate >130 b.p.m. or <45 b.p.m.), respiratory distress (respiratory rate >25/min; peripheral oxygen saturation <90%), or signs of tissue hypoperfusion with abnormal cellular oxygen metabolism (increased blood lactate >2.0 mmol/L; low central–venous oxygen saturation <60%, if available; altered mental state; cold, clammy, mottled skin; oliguria <0.5 mL/kg/h).1, 7 Since PPCM is a diagnosis of exclusion, several additional tests should be performed (see below). This should not delay the start of treatment, which should be instituted as soon as AHF is confirmed. An ECG should be performed in all patients with suspected PPCM as it has high negative predictive value and might help in identifying the cardiac origin of dyspnoea. Indeed, despite the fact that no specific ECG pattern for PPCM seems to exist, at initial evaluation, the ECG is rarely normal and repolarization abnormalities are common.4, 8, 9 Patients with acute PPCM usually have elevated plasma concentrations of natriuretic peptides.10, 11 Measurement of natriuretic peptides may help during screening for identifying a cardiac origin of dyspnoea, although it does not help in the differentiation of PPCM from other cardiomyopathies. More specific biomarkers would be helpful to allow a faster and more reliable diagnosis of PPCM, but these are yet to be adequately defined. Echocardiography is indicated as soon as possible, in all cases of suspected PPCM to confirm the diagnosis, assess concomitant or pre-existing cardiac disease, exclude complications of PPCM (e.g. LV thrombus), and obtain prognostic information. Cardiac magnetic resonance imaging (MRI) is not routinely needed, but can be performed after stabilization in cases where additional information, not available with echocardiography, is needed. However, administration of gadolinium to assess late enhancement should be avoided until after delivery, unless absolutely necessary. Endomyocardial biopsy does not add any diagnostic or prognostic information in the case of PPCM but can be used to exclude acute myocarditis after delivery. Only a few PPCM cases have been related to myocarditis so far,12 but myocarditis may underlie cases of dilated cardiomyopathies and AHF that can occur or worsen during pregnancy, and specific immunosuppressive or immune-modulatory treatments may be helpful for some forms of myocarditis.13 The management of heart failure around pregnancy is challenging (Box 1), and, in the absence of evidence-based data, the initial management of patients with PPCM is similar to the treatment of AHF of other aetiologies.14, 15 Interdisciplinary approaches of cardiologists, intensivists, obstetricians, neonatologists, anaesthetists, and cardiac surgeons are necessary in cases of severe AHF. Pre-specified protocols of interdisciplinary work-up of these patients are helpful (Figure 1).16 Timely diagnosis and treatment delivery are crucial. Figure 2 summarizes the recommended treatment algorithm for patients with acute PPCM. Of note, the initial treatment of patients with severe forms of acute PPCM is significantly different from that of stable patients. Patients with signs of cardiopulmonary distress and/or circulatory shock need rapid and more aggressive therapy and should be admitted to the intensive cardiac care unit. Initial therapy includes five main elements: optimization of the preload; optimization of oxygenation; restoration of haemodynamics with inotropes and/or vasopressors; urgent delivery if heart failure occurs during pre-partum; and consideration of adjunctive therapies with bromocriptine (2.5 mg twice daily for 2 weeks followed by 2.5 mg per day for 6 weeks). Optimization of preload includes, depending on the clinical scenario, administration of fluids or diuretics. If there is no sign of overt fluid overload, a fluid challenge (250–500 mL over 15–30 min) is recommended, especially in patients with intravascular depletion secondary to peripartal blood loss or overaggressive diuretic therapy. In the presence of signs of congestion, intravenous diuretics should be administered. In patients with systolic blood pressure >110 mmHg, intravenous vasodilators (e.g. nitrates) should be started. At the same time, oxygenation should be optimized (target peripheral oxygen saturation, SpO2 > 95%). Non-invasive ventilation (NIV) reduces respiratory distress and may decrease intubation and mortality rates.17 Intubation with mechanical ventilation should be considered in the case of altered mental state or persistent hypoxaemia. In the presence of signs of cardiogenic shock, haemodynamics should be rapidly restored to avoid irreversible organ damage. Inotropes and vasopressors may be considered, although the use of catecholamines is associated with adverse effects in patients with advanced heart failure or cardiogenic shock.18, 19 Experimental evidence and clinical experience suggest that catecholamines such as dobutamine are less favourable in PPCM patients due to metabolic compromise.20 Therefore, catecholamines should be avoided whenever possible or used only with extreme caution. Levosimendan, in contrast to dobutamine and adrenaline, does not increase myocardial oxygen demand and may be considered as the preferred inotropic agent as continuous infusion of 0.1 µg/kg/h for 24 h without an initial loading dose (bolus) for patients with severe PPCM.21 A recent small study including 28 patients showed that the use of levosimendan in patients with PPCM induced rapid haemodynamic recovery and profound decongestive effects.22 In case levosimendan is unavailable, dobutamine is the other option, while adrenaline should be avoided. As for other causes of shock, noradrenaline should be the first-line vasopressor. Patients with haemodynamic instability despite treatment should undergo urgent delivery irrespective of gestation duration. Caesarean section with combined spinal and epidural analgesia and involvement of an experienced interdisciplinary team are recommended. The administration of adjunctive therapies with the prolactin blocker bromocriptine has shown promising results in several case series and in a small proof-of-concept study,23 and should be considered for patients with cardiopulmonary distress. The starting dose of bromocriptine is usually 2.5 mg twice daily, but an increased dose may be necessary to lower prolactin levels in selected cases (see below). As thrombo-embolic events have been reported during the use of bromocriptine (albeit mostly at higher dosages), bromocriptine treatment should always be accompanied by at least prophylactic anticoagulation with heparin.24 Anticoagulation with heparin should also be started in all patients with acute PPCM and severely reduced LV systolic function (LVEF ≤35%). Indeed, the combination of reduced EF and the procoagulant activity during the peripartal phase exposes patients to a clinically important risk of cardio-embolic events. In general, patients with severe distress should be transferred early to an experienced centre whenever possible. For patients with persistent haemodynamic instability despite medical treatment, mechanical circulatory support should be considered (see below). Implantation of a mechanical circulatory support should be considered early as a rescue therapy in patients who cannot be stabilized with medical therapy alone. If necessary, a device for temporary support should be implanted in the acute phase, either as ‘bridge-to-recovery’, if ventricular function improves during the subsequent days and weaning can be achieved, or as ‘bridge-to-bridge’, if haemodynamic impairment persists and circulatory support has to be ensured by switching to a more durable (and usually more invasive) device. Because of the higher proportion of patients with at least partial recovery of ventricular function compared with other cardiomyopathies, an initial ‘bridge-to-transplantation’ strategy is seldom necessary. Since several devices exist, and there is little evidence about which device should be preferred;25 we provide here an overview of some devices based on experts' opinion. For the choice of the initial device, several factors should be taken into account (needed haemodynamic support, periprocedural risks, costs), but the oxygenation status of the patient plays a central role. If the patient is adequately oxygenated, percutaneous [e.g. intra-aortic balloon pump (IABP), Impella®] or surgical (e.g. CentriMag®, AbiomedBVS 5000®) devices can be used to restore circulation. In contrast, in the presence of impaired oxygenation, other devices with integrated oxygenation should be used [e.g. TandemHeart®, veno-arterial extracorporeal membrane oxygenation (ECMO)]. Most importantly, as the treatment of patients on mechanical circulatory support is very challenging, the choice of the device should also consider the local availability and the experience of the involved care team (physicians, nurses, and perfusionists). Percutaneous devices offer the advantage of fast and easier placement and removal without the need for open surgery, but complications related to the access site (bleeding, infection, ischaemic limbs) are not uncommon. An IABP provides less haemodynamic support compared with other devices, but on the other hand is easily placed and needs less strict anticoagulation. Given the negative results of the IABP-SHOCK II trial and the lack of data in PPCM, the value of this device in patients with severe PPCM is uncertain, although it is used in selected cases by some centres.26 The Impella® rotary pump is an alternative percutaneous device for temporary support. It is inserted percutaneously from the femoral artery and is placed in the left ventricle through the aortic valve. Depending on the model, it provides a higher degree of haemodynamic support compared with IABP (up to 5 L/min) but is associated with haemolysis and, especially in the context of PPCM, where a procoagulant state is frequent, a stricter anticoagulation regime than for IABP is needed.27 In a small trial in patients with cardiogenic shock complicating myocardial infarction, there was no difference in terms of survival between IABP and Impella®.28 Clinical experience in several PPCM patients with the Impella 3.5 device suggests effective LV support over up to 7–10 days when used as bridge-to-recovery in most patients. The marked decrease in the need for catecholamines may importantly contribute to the beneficial outcome observed in several patients (Figure 3). The TandemHeart® device offers similar haemodynamic support to Impella® (up to 5 L/min) with additional improvement in oxygenation. The placement of this device is performed percutaneously in the catheterization laboratory but it requires a more complex placement with atrial trans-septal puncture. No evidence of improved outcomes in patients with cardiogenic shock receiving TandemHeart® compared with IABP exists.29, 30 Extracorporeal membrane oxygenation with veno-arterial cannulation offers the maximal available haemodynamic effect with biventricular support and additional improvement in oxygenation.31 As increased prolactin levels during ECMO treatment have been reported, which may be specifically detrimental in patients with PPCM,32 effective suppression of prolactin under sequential measurements of prolactin levels could be considered in this particular situation with bromocriptine doses up to 10 mg twice daily. After the initial phase, if no weaning from mechanical circulatory support can be achieved after a maximum of 7–10 days, a switch to a durable device should be planned. As for temporary support, several devices exist and little evidence is available to guide the choice of the optimal device. Special attention should be paid to right ventricular function. In the presence of impaired right ventricular function, a biventricular assist device (BiVAD or total artificial heart) may be chosen (e.g. Berlin Heart EXCOR®). Alternatively, several strategies of transient right ventricular support in patients after left ventricular assist device (LVAD) implantation have been adopted in different centres (e.g. veno-arterial ECMO, Impella® RP, or similar). In patients with preserved right ventricular function, LVADs should be preferred. The most commonly used devices are the continuous-flow axial (HeartMate II®) and centrifugal (HeartWare®) LVADs which have shown promising results in patients with end-stage heart failure.33-35 Given the high likelihood of at least partial recovery of ventricular function in PPCM, temporary devices should always be the preferred initial strategy. Cardiac transplantation is reserved for patients where mechanical circulatory support is not possible or satisfactory ventricular recovery after 6–12 months is not achieved. Post-transplant outcomes in women with PPCM appear to be worse than in other recipients: in particular, women with PPCM show higher mortality, a higher incidence of rejection with shorter graft survival, and higher rates of re-transplantation.36 The initial treatment of patients with confirmed PPCM without cardiopulmonary distress depends on the time point of onset. Patients who present after delivery should be treated according to the ESC guidelines for heart failure.37 For patients presenting during pregnancy, joint cardiac and obstetric care in observance of the ESC guidelines for management of cardiovascular diseases in pregnancy is recommended.38 During pregnancy, ACE inhibitors, ARBs, and renin inhibitors are contraindicated because of foetal toxicity. and can be used After delivery, ACE inhibitors can be but during or should be preferred. an increased risk of foetal are indicated in all patients in stable with the preferred should be avoided during pregnancy and but should be started in stable patients. should be with during pregnancy as may of the for use during pregnancy and are in of the ESC guidelines for management of cardiovascular diseases in in to heart failure therapy should be considered because it has shown promising results with improved LV systolic function and clinical outcomes in several case series and in a small proof-of-concept In the PPCM treatment with ACE inhibitors, and bromocriptine (2.5 mg twice daily for 2 weeks followed by 2.5 mg per day for 6 was associated with favourable A study with patients randomized to either or long-term treatment with bromocriptine has patient and results will be available in the Anticoagulation with heparin should be started in all patients with acute PPCM treated with bromocriptine and in with severely reduced LV systolic function (LVEF diuretics should be when possible after stabilization and when ACE inhibitors, and should be in and not during the first months after recovery of LV and systolic function. of heart failure therapy might be considered if both recovery of ventricular function and normal are achieved. should be according to early treatment with or in with may be considered, as it to be and effective (Figure As have been observed after of the heart failure drugs should be performed under of systolic and obstetric management including on the risk of PPCM with is recommended. knowledge about the and pathophysiology of PPCM, mortality rates are not and may from up to It is that about a of are by ventricular mostly occurring during the first 6 and optimal management may a of impaired ventricular function is associated with increased risk of ESC guidelines for the treatment of heart failure implantation of an for in patients with heart failure and despite optimal treatment or for secondary in patients with ventricular haemodynamic In the context of PPCM, where young women with the for recovery of ventricular function are about implantation of an should be taken with caution. After diagnosis of PPCM, are with the about the subsequent of ventricular function. 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