Learning Objectives:After participating in this continuing education activity, the provider should be better able to:
1. Identify the diagnostic criteria for peripartum cardiomyopathy.
2. Differentiate peripartum cardiomyopathy from other clinical entities.
3. Develop a treatment plan for a patient with peripartum cardiomyopathy.
Peripartum cardiomyopathy (PPCM) is a life-threatening complication that typically presents as systolic heart failure in otherwise healthy women toward the end of pregnancy or in the months immediately after delivery. In the United States, the incidence of this condition is 1 in approximately 3000 live births and disproportionally affects African American women.1 It is considered a diagnosis of exclusion when no other causes of heart failure can be identified and is associated with significant morbidity and mortality.1 However, due to the variability in its clinical presentation and similarities to other conditions of pregnancy, PPCM can be challenging to diagnose. Furthermore, the pathophysiology of PPCM remains unclear. However, many promising theories have recently been proposed, guiding the development of novel treatments for the near future. For these reasons, the goals of this review are to describe the clinical presentation and diagnostic criteria for PPCM, provide a summary of promising hypotheses regarding its pathophysiology, and outline the current management options for this condition.
Clinical Presentation and Diagnosis
The National Heart, Lung, and Blood Institute (NHLBI) defines PPCM as the onset of clinical heart failure in the last month of pregnancy or within 5 months after delivery.2 The NHLBI and the European Society of Cardiology also include the absence of identifiable cause for cardiac failure, absence of recognizable heart disease before the last month of pregnancy, and left ventricular ejection fraction (LVEF) less than 45% on echocardiography as potential diagnostic criteria.3 Common symptoms of PPCM include dyspnea, orthopnea, peripheral edema, paroxysmal nocturnal dyspnea, palpitations, chest pain, decreased exercise tolerance, and a persistent cough.2 On examination, these patients may exhibit symptoms consistent with both right and left heart failure. Cardiovascular examination may be notable for a loud P2, an S3 or gallop rhythm, new-onset mitral or tricuspid regurgitation, jugular venous distension, and a hepatojugular reflux.2 Other examination findings include tachypnea, bilateral pulmonary rales, hepatomegaly, peripheral edema, and ascites. Most notably, blood pressure usually remains normal in this disease course.2
Various laboratory, imaging, and electrocardiogram (EKG) findings can also help support a diagnosis of PPCM in a patient for whom the clinical index of suspicion is high. Inflammatory markers, such as C-reactive protein (CRP), may be mildly elevated in pregnant patients, but present significantly elevated in patients who develop PPCM.3,4 Similarly, although mild physiologic elevations in brain natriuretic peptide (BNP) are seen during pregnancy, significant elevations can aid the diagnosis of PPCM.4 The EKG of a patient with PPCM may exhibit either sinus rhythm or nonspecific ST-segment and T-wave abnormalities. Q waves, AV-conduction abnormalities, and ectopic beats may also be noted.2
Similar to other forms of cardiomyopathy, a chest x-ray typically shows left ventricular (LV) enlargement and pericardial effusion, with occasional pulmonary venous congestion, interstitial infiltrates, and pleural effusion depending on severity.3 Echocardiography is essential in the diagnosis of PPCM, as an LVEF less than 45% is a diagnostic criterion for this disease. Cardiac MRI, similarly, is rising in popularity as a tool for evaluating PPCM and confirming findings seen on echocardiography, given the lack of radiation exposure.1
Of note, although the presentation of PPCM is similar to that of hypertensive disorders of pregnancy, such as hypertensive heart failure of pregnancy (HHFP), it is a distinct and separate disease process.5 In fact, many recent studies have shown distinct differences in clinical course, echocardiographic features, and outcomes between PPCM and HHFP.5 Patients with HHFP typically present with isolated pulmonary edema without other clinical features of congestive heart failure and tachycardia and hypertension.5
On echocardiography, patients with HHFP also exhibit increased thickness of their interventricular septum and LV free wall compared with those with PPCM, indicating a disease process secondary to chronically elevated blood pressures rather than an alternative cause.6 Perhaps most importantly, patients with PPCM have been found to have a significant increase in morbidity and mortality compared with those with HHFP, underscoring the need to identify these patients appropriately.6
Pathophysiology
Many theories have been proposed in the literature as to the underlying cause of PPCM. Given the significant predominance of PPCM in certain ethnic groups and particular geographic regions, a genetic predisposition to this disease has been proposed.7 The incidence of peripartum cardiopathy in Haiti, for instance, has been estimated to be as high as 1 in 400, whereas the overall incidence of PPCM is 1 in 4000 deliveries.8,9
Recent studies have demonstrated that mutations in key genes such as TNNC1 and TNNT2 were commonly found in families with multiple relatives who developed PPCM.10 In fact, carriers of these mutations often had first-degree relatives who also developed PPCM.10 It is suspected that the greater physiologic stress imposed by pregnancy often exposes the genetic predisposition in these patients to developing cardiomyopathy and triggers its development.7
Alternative theories focus on imbalances in cardiac angiogenic factors, such as vascular endothelial growth factor (VEGF), as a primary driving factor for PPCM.7 During late gestation, the placenta is known to secrete VEGF inhibitors, such as soluble fms-like tyrosine kinase-1 (sFLT-1).11 Elevated levels of sFLT-1 have been implicated as a potential cause of preeclampsia, and recent murine model studies have indicated that this pathway may be implicated in PPCM pathogenesis as well.11 In these models, PPCM was even ameliorated by the addition of recombinant VEGF to overcome the effects of sFLT-1.11 Taken together, this model suggests that PPCM may occur as a consequence of damaged placenta vasculature, leading to impaired blood flow.
Additional factors that are essential in regulating the late gestational period, such as prolactin, have also been implicated as a possible mechanism for PPCM pathogenesis.7 The 16-kDa form of prolactin, known as vasoinhibin, has been shown to be a strong antiangiogenic factor.12 It is suspected to work by inducing endothelial cell cycle arrest at the G0-G1 and G2-M stages and concurrently inducing apoptosis through the caspase and nuclear factor-[kappa]B (NF-[kappa]B) pathways.12 Further still, it has been shown to increase leukocyte adhesion, promote inflammation, and increase oxidative stress.12 In the initiation and progression of PPCM, 16 kDa has been further implicated through studies that have shown that use of D2 receptor agonists, such as bromocriptine, prevents the onset of PPCM in murine models that are genetically predisposed to develop it.12 Although large randomized control trials have not yet been conducted to assess the clinical relevance of this data, small clinical studies in Germany show promise for this model.12
Lastly, inflammatory cascades, such as the PI3-Akt pathway, have been shown to be strongly activated in patients with PPCM.7 Although this pathway has been hypothesized to be cardioprotective early in pregnancy, given its proposed correlation with physiologic cardiac hypertrophy, its activity rapidly decreases after delivery, as the mechanical stressors no longer exist.7 Continued activation of this pathway in the peripartum period has been seen in murine models of PPCM and has been associated with systolic dysfunction, cardiac hypertrophy, and reduced capillary density.7 Interestingly, studies involving the use of dopamine agonists such as bromocriptine have also shown downregulation of this pathway associated with its use and a resultant prevention of heart failure.7
Management Strategies
The treatment of PPCM is comparable to the management of systolic heart failure due to any other cause. However, the appropriate treatment regimen is dependent on the severity of disease on presentation and whether the patient is pregnant or postpartum. Patients who present with signs of acute heart failure should initially be offered supplemental oxygen and/or further respiratory support as needed.2 Further pharmacologic intervention for acute heart failure should be carefully considered in patients who are pregnant, as little data exist on the safety of heart failure medications during the peripartum period. Diuretics, for instance, have been associated with decreased placental flow.1 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers have also been associated with renal dysplasia, oligohydramnios, and intrauterine growth restriction.1,13 Long-term use of [beta]-blockers has been associated with fetal bradycardia and low birth weight, although preliminary data suggest that short-term use may be safe.1 Aldosterone antagonists have also been associated with antiandrogenic effects on the fetus, and should thus be avoided.1 Medications that have been deemed safe for use during pregnancy include hydralazine, nitrates, and digoxin, although levels of digoxin should be monitored closely for toxicity.2 If anticoagulation is required, the use of unfractionated heparin and low-molecular-weight heparin has been deemed safe during the first trimester and just before delivery.14 Warfarin administration should be avoided given its potential for teratogenic effects at any time during the pregnancy.14 Although anticoagulation is not indicated for all patients with PPCM, it should be considered for any patient who presents with an LVEF less than 35%.14
In addition to the medications discussed, lifestyle modifications should be a mainstay of any treatment regimen for PPCM patients who present with chronic heart failure.14 These include a sodium-restricted diet, weight loss, exercise as tolerated, and smoking cessation, if applicable.14 Additional modalities of treatment, which may be considered in patients with PPCM, include implantable cardioverter-defibrillators (ICDs) and cardiac assist devices.1 As arrhythmias are common in the postpartum period of PPCM patients, ICDs should be considered in those patients who exhibit persistent LV dysfunction despite medical management.1 Alternatively, wearable external defibrillators or subcutaneous ICDs may be used as a bridge for an implantable device for patients who are high risk.1 Similarly, patients who present with the greatest severity of disease and do not respond to medical therapy may be provided with cardiac assist devices, such as intra-aortic balloon pumps, extracorporeal membrane oxygenation, and LV assist devices, particularly if they are deemed to require cardiac transplantation after the delivery.1
Early delivery should be considered in women who are clinically deteriorating as a result of their poor cardiac function.15 However, it is not indicated in patients who are otherwise clinically stable on their therapeutic regimen. Additionally, due to the potential for hemodynamic instability during a cesarean delivery and inherent risk of cardiac depression associated with general anesthesia, vaginal delivery should be preferentially pursued over cesarean delivery when possible.15,16 In the setting of a vaginal delivery, maternal effort should be reduced as much as possible through assistance during the second stage of labor.1 Furthermore, maternal and fetal hemodynamic status should be closely monitored throughout the delivery, as patients with PPCM may be particularly sensitive to blood loss.1 After delivery, given the proposed role of prolactin and negative effects of 16-kDa fragments, patients should be discouraged from breastfeeding if possible.1 If patients elect to proceed with breastfeeding, they should be advised against using the heart failure medications described earlier, as little data exist about their safety in breastfeeding patients.1
Conclusion
PPCM is a critical complication of pregnancy, which is associated with significant morbidity and mortality. A comprehensive understanding of the clinical presentation is imperative for early diagnosis. Although the underlying pathophysiology is not fully understood at this time, numerous hypotheses are under active investigation to elucidate it further. Lastly, management of PPCM should involve a multimodal approach with both pharmacologic and nonpharmacologic treatment options and should be tailored to each patient based on the presence or absence of pregnancy and disease severity.
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