|Year : 2018 | Volume
| Issue : 2 | Page : 54-59
Peripartum cardiomyopathy: A contemporary review
Akshai Bhandary MD , Tarak Rambhatla MD , Neil Coplan MD , Itzhak Kronzon MD
Department of Cardiovascular Medicine, Lenox Hill Hospital, Northwell Health, New York, NY, USA
|Date of Web Publication||23-Mar-2018|
Dr. Itzhak Kronzon
Hofstra College of Medicine, Lenox Hill Hospital, New York, NY
Source of Support: None, Conflict of Interest: None
Peripartum cardiomyopathy (PPCM) is a rare, potentially life-threatening disorder affecting women in late pregnancy and the postpartum period. Historically, PPCM was not recognized as a separate disease entity until the 1930s. Further research has since led to the identification of at-risk demographics, theories on etiology, and new targets of therapy. Management to date has largely been focused on guideline-based treatment for heart failure with reduced ejection fraction. However, newer studies have shown the efficacy of novel therapies. In this article, we will review the pathogenesis and diagnosis of PPCM and conclude with some of the newest therapies being offered.
Keywords: Cardiomyopathy, dilated cardiomyopathy, heart failure, reduced ejection fraction
|How to cite this article:|
Bhandary A, Rambhatla T, Coplan N, Kronzon I. Peripartum cardiomyopathy: A contemporary review. J Clin Prev Cardiol 2018;7:54-9
| Introduction|| |
Congestive heart failure (HF), occurring during the peripartum period, was first described in 1849. However, it was not until the 1930s when it was officially recognized as a clinical entity occurring as a consequence of pregnancy. In the 1970s, a 20-year experience following 27 patients who developed cardiomegaly in the puerperium was published, and the term peripartum cardiomyopathy (PPCM) was established by Demakis and Rahimtoola in 1971. Since then, we have developed a greater understanding through data collection and improved diagnostic methods resulting in PPCM becoming a well-defined form of HF. Today, PPCM remains a rare yet significant cause of maternal morbidity and mortality. The purpose of this review is to summarize the current data concerning epidemiology, etiology, proposed pathomechanisms of PPCM, diagnosis, and new strategies for therapy and prognosis.
| Definition|| |
Since PPCM was first recognized, the exact definition has been subject to debate. Specifically, the timing of HF related to pregnancy and the interval cutoffs that would be used. The first proposed criteria by Demakis and Rahimtoola were (1) development of cardiac failure in the last month of pregnancy or within 5 months of delivery, (2) absence of another etiology of HF, and (3) the absence of cardiac disease before pregnancy. Following this, in 1997, the National Heart, Lung, and Blood Institute and the Office of Rare Disease of the National Institutes of Health adopted these three criteria and incorporated echocardiographic criteria. They proposed the addition of left ventricular systolic dysfunction with a left ventricular ejection fraction (LVEF) <45%, a fractional shortening <30%, or both with or without an LV end-diastolic dimension >2.7 cm/m 2. In 2010, The European Society of Cardiology working group on PPCM released a modified definition with adjustments to time specifications and LV dimensions of PPCM. They stated that PPCM is an idiopathic cardiomyopathy presenting with HF toward the end of pregnancy or in the months following delivery, where no other cause of HF is found, where the LV may or may not be dilated, but the EF is nearly always <45%. This intentional ambiguity of the time cutoffs was an effort to avoid underdiagnosis of this condition. As we will go on to describe, a multitude of factors contribute to delay in diagnosis of PPCM and early recognition of this condition is central to the patient's well-being.
| Epidemiology|| |
With regard to the incidence of PPCM, there has been a wide geographic variation that has been observed. The reported incidence of PPCM in the United States alone has reflected this and has ranged from 1/4075, 1/3180, to 1/2066. The incidence in other parts of the world appears to be higher. Specifically in Haiti observed incidence with roughly 1/300 live births. In addition, other countries have also shown increased incidence when compared to the US: 1/1000 in South Africa, 1/102 in Nigeria, 1/837 in Pakistan, and 1/1374 in South India. From the limited studies available, there appears to be great variability among different ethnicities. Further prospective studies would serve well to better identify high-risk populations.
| Risk Factors|| |
Multiple risk factors have been implicated in the development PPCM such as African-American ethnicity, age, preeclampsia, multiparity, multiple gestations, obesity, chronic hypertension, and the prolonged use of tocolytics. However, African-American ethnicity appears to confer the highest risk of any of these. A study conducted between 1996 and 2005 reviewed 241,497 deliveries and found the overall incidence of PPCM to be 1 in 4025 deliveries. Furthermore, the study revealed that African-Americans had the highest incidence of PPCM occurring in 1 out of every 1421 births, compared to the rates in Asians (2675), Caucasians (4075), and Hispanics (9861). In a study using the National Hospital Discharge Survey, 16,296 cases of PPCM were reviewed, and 32.2% of patients were African-American. In a nationwide database survey for all patients aged 15–54 with the diagnosis of PPCM, the largest proportion of patients were African-American (47.5%). Not only are African-American women more prone to developing PPCM but are also more likely to develop it at an earlier age, present later in the pregnancy, and less likely to have a full recovery of LV function.
Age is another risk factor that occurs with greater frequency. The average age of mothers that developed PPCM was found to be higher than the average age of mothers who did not, 29.7 years versus 26.9. There also seems to be a further increase in risk with increasing age, with the incidence of 36.7/10,000 live births for a mother aged 40–54 years of age versus 10.3/10,000 live births for mothers of all ages.
| Etiology/pathogenesis|| |
The exact underlying mechanism of PPCM remains unknown. There have been numerous proposed causes including hormonal abnormalities, inflammation, viral pathogens, autoimmune response, and genetic predisposition.,,,, Numerous contributing factors have been documented including the traditional risk factors for cardiovascular disease: hypertension, diabetes, and smoking. Other associated factors, specifically those related to pregnancy, have also been thought to play a role such as number of pregnancies, induction agent, and malnutrition.
Prolactin, 16 kDa prolactin, and cathepsin D
It is has been shown that pregnancy is associated with an increase in oxidative stress that is accompanied by a delay in antioxidant capacity. Hilfiker-Kleiner et al. reported findings in 2007, in which investigators were able to recreate this discrepancy in antioxidant capacity through an experimental mouse model. Investigators were able to show that female mice with cardiomyocyte-restricted knockout of the STAT3 protein resulted in diminished expression of manganese superoxide dismutase, an enzyme that plays a role in neutralizing reactive oxygen species. This environment of increased oxidative stress led to the release of the prolactin-cleaving protease and cathepsin D. Cathepsin D, in turn, cleaves the hormone prolactin from its 23 kDa form to its 16 kDa form. This 16 kDa isoform of prolactin has been shown to have deleterious effects on the cardiovascular system such as induction of endothelial cell apoptosis, capillary dissociation, and vasoconstriction which disrupts cardiomyocyte metabolism and function resulting in PPCM., This cascade of events was further supported by the use of bromocriptine, an inhibitor of prolactin secretion, which was shown to prevent the development of PPCM in these mice.
While the role of oxidative stress in the development of PPCM has been better defined, inflammation may also contribute. Serum markers of nonspecific inflammation such as the soluble death receptor sFas/Apo-1, C-reactive protein, interferon gamma, and interleukin-6 have all been shown to be elevated in patients with PPCM.,,, This concept was further supported by the clinical benefit of pentoxifylline, an anti-inflammatory agent, in a nonrandomized trial of 59 patients with PPCM. The patients were divided into two groups. Group 1 (29 patients) treated with standard of care regimen (diuretics, digoxin, enalapril, and carvedilol), while Group 2 (30 patients) received pentoxifylline 400 mg TID in addition to standard of care. They found that the pentoxifylline group had significantly better outcomes. More specifically pentoxifylline was the only independent predictor of outcome (P < 0.04) in this study.
The role of viral pathogens in PPCM has not been well defined. It is generally recognized that pregnancy represents a state of compromised immunity. This leads to an increased susceptibility not only to newly acquired viruses but also to reactivation of latent viruses. One small study looked at the presence of viral genomes in cardiac tissue of 26 PPCM patients by polymerase chain reaction testing on endomyocardial biopsy specimens. Eight of these patients (30.8%) were found to have detectable viral genomes associated with histologic evidence of inflammation. Viruses identified in these PPCM patients included Epstein–Barr virus, human cytomegalovirus, human herpesvirus 6, and parvovirus. However, in a review conducted by Selle et al., the prevalence of viral myocarditis in PPCM patients was much more variable, ranging from 8.8% to 78%. While these studies highlighted the prevalence of viral pathogens in this population, the exact role in the development of PPCM and its impact on prognosis has yet to be well understood. Further investigation with large, prospective studies would be required to elucidate this relationship.
By definition, PPCM has been identified as a nongenetic/nonfamilial form of dilated cardiomyopathy (DCM). However, multiple studies have shown evidence of familial clustering suggesting the possibility of genetic predisposition.,,, In a study by Morales et al., they reviewed a registry containing 520 families with nonischemic DCM identifying 19 cases that met criteria for PPCM. These patients were then tested for known DCM genes revealing five testing positive for genetic mutations. Three cases were familiar with mutations found in MYH7, SCN5A, and PSEN2, and two were sporadic with mutations occurring in MYH6 and TNNT2. In a similar study, van Spaendonck-Zwarts et al. reviewed 90 families from a familial dilated cardiomyopathy (FDC) registry. They identified 5 (6%) families with patients who met the criteria for PPCM. One of these PPCM patients was found to have a mutation associated with the TNCC1 gene which codes for cardiac troponin C. Using the same FDC registry, they reviewed 10 patients with PPCM that had been following with them since the early 1990s. Of these 10 patients, three of them had not shown full recovery of LV function despite optimal medical therapy. They then screened the first-degree relatives of these three patients revealing undiagnosed DCM in all three families. These findings suggest that at least in a subset of PPCM patients there is an underlying genetic etiology. These findings could have implications concerning family counseling and prognosis going forward.
| Clinical Presentation|| |
The presentation of PPCM patients is highly variable. Patients may range from mildly symptomatic to the New York Heart Association (NYHA) Class IV. Furthermore, a high index of suspicion is required when making the diagnosis of PPCM given the significant overlap of symptoms related to early PPCM compared to the expected physiologic changes associated with pregnancy. Signs and symptoms such as pedal edema, dyspnea on exertion, orthopnea, and persistent cough are common in pregnancy or other pregnancy-related pathologies (i.e., anemia) which can lead to delay in diagnosis. However, the most common initial presentation is NYHA functional Class III or IV. Some patients may even present with ventricular arrhythmias or cardiac arrest. In addition, pregnancy is known to be a hypercoagulable state. This in combination with an LVEF ≤35% increases the risk of LV thrombus formation., Initial presentations with systemic embolism including cerebrovascular disease, mesenteric ischemia, and myocardial infarction have been reported., The majority of patients (78%) present in the postpartum period, typically within the first 4-month postdelivery. Only 9% of patients presented in the final month of pregnancy, while the remaining 13% either presented before the last month of pregnancy or more than 4 months postpartum.
Physical examination signs in PPCM are typical of other forms of HF with systolic dysfunction. Physical examination typically reveals tachycardia, tachypnea, jugular venous distension, displaced apical impulse, murmurs of mitral and tricuspid regurgitation, third heart sound (S3), pulmonary rales, hepatosplenomegaly, ascites, and peripheral edema.,
| Diagnosis|| |
PPCM should be approached from a diagnostic standpoint as you would any new-onset HF. However, PPCM remains a diagnosis of exclusion and both cardiac and noncardiac causes, specifically those related to the complex physiologic changes of pregnancy must be ruled out. Combined with a thorough history and physical examination, initial workup should include a 12-lead electrocardiogram (ECG), two-dimensional echocardiogram, chest X-ray, and routine laboratory tests including complete blood count, basic metabolic panel, liver function tests, thyroid function tests, and urinalysis.
A 12-lead ECG should be performed in the initial assessment of all patients with suspected PPCM. In one study looking at point-of-diagnosis ECGs of 78 South African PPCM patients, 75 (96%) were found to have an ECG abnormality or variant. While major ECG abnormalities (pathologic Q-waves, ST depression, T-wave inversion, 2nd- or 3rd-degree atrioventricular block, complete left or right bundle branch block, atrial fibrillation or flutter, and frequent atrial or ventricular ectopy) occurred in 38 (49%) patients. The two most common abnormalities overall were T-wave anomalies (38%) followed by QRS axis (26%). Despite ECG abnormalities being common, a normal ECG does not rule out PPCM.
The performance of a transthoracic echocardiogram (TTE) is central to the diagnosis of PPCM. TTE is used to establish a reduced LVEF (<45%), needed for the diagnosis, while also helping to rule out other causes of HF. TTE is also useful in ruling out LV thrombus. In addition to its diagnostic value, LV end-diastolic diameter (>60 mm) and LVEF <30% have been cited in multiple studies as predictors of poor recovery of LV function.,,
Cardiac magnetic resonance imaging
While TTE remains the most widely used diagnostic test in PPCM, cardiac magnetic resonance imaging (MRI) has been shown to be more accurate in measuring chamber size and LV function when compared to echocardiography. MRI also has a higher sensitivity in detecting LV thrombus. Although PPCM does not have any specific pattern of gadolinium enhancement, this technique is useful in excluding myocarditis and other forms of infiltrative disease.
Echocardiography should be repeated before discharge from the index hospitalization. That should be followed by a TTE at 6 weeks, 6 months, and then annually to assess response to medical therapy. If MRI is the imaging modality of choice, it should be repeated at 6 months and 1-year postdischarge.
N-terminal Pro-BNP (NT-proBNP) is the most widely used serum marker in PPCM. While it is not very specific for PPCM, it has good sensitivity and provides efficient screening for patients with PPCM., In one study, 38 patients diagnosed with PPCM all had elevated NT-proBNP levels (mean 1727.2 fmol/ml) compared to 21 healthy, postpartum patients with normal NT-proBNP levels (mean 339.5 fmol/ml). Other markers such as microRNA-146a, cathepsin D, and interferon-gamma among others have been shown to have both diagnostic and prognostic value.,,,, However, lack of availability, prohibitive costs, and the need further investigation have limited their use. The challenges in diagnosis specified earlier highlight the demand for a more specific serum marker in PPCM.
| Treatment|| |
Initial therapy for PPCM is similar to that of other forms of DCM with respect to medications that can be safely administered during pregnancy. Most notably angiotensin-converting enzyme (ACE) inhibitors, a mainstay of HF therapy in patients with reduced EF, should not be used during the 2nd or 3rd trimester. Otherwise, goal directed medical therapy for HF should be instituted, with preference given to selective beta antagonists (B-1) such as metoprolol succinate. β-2 receptor antagonism has been shown to have an antitocolytic effect. Nitrates and hydralazine are both safe for use during pregnancy, while loop diuretics can be used as needed for symptoms of volume overload. In patients presenting with fulminant HF with signs and symptoms of cardiogenic shock and/or low-output state – inotropes (i.e., dobutamine) should be initiated without delay. If LV thrombus is detected, then anticoagulation should be started. Heparin, either unfractionated or low-molecular weight, is preferred during pregnancy since it does not cross the placental barrier. Warfarin is contraindicated throughout pregnancy and is considered highly teratogenic.
Bromocriptine is by far the most promising of the novel therapeutic strategies for PPCM. Earlier described was the cascade of events initiated by oxidative stress resulting in increased levels of the pro-apoptotic and angiostatic 16 kDa prolactin. Bromocriptine is a D2 dopamine agonist that suppresses the production of prolactin. In 2010, Hilfiker-Kleiner et al. published a proof of concept study, in which 20 newly diagnosed PPCM patients were randomized to standard of care versus standard of care plus 8 weeks of bromocriptine. The bromocriptine group showed the greater return of LV function at 6 months. While the study was underpowered, the results were promising. Currently, a large, prospective randomized control trial (NCT00998556) is being conducted in 11 centers across Germany. Results from this trial will further elucidate the potential benefit of bromocriptine in PPCM.
Pentoxifylline is an anti-inflammatory drug known to inhibit the production of TNF-a, a marker of inflammation. In 2002, Sliwa et al. published the results of a nonrandomized trial of 59 patients with PPCM. The patients were divided into two groups with Group 1 (29 patients) treated with standard of care regimen (diuretics, digoxin, enalapril, and carvedilol), while Group 2 (30 patients) received pentoxifylline 400 mg TID in addition to standard of care. They found that a combined endpoint of poor outcome defined as either death, failure to improve the LVEF >10 absolute points or NYHA Class III or IV at latest follow-up, occurred in 52% of patients in Group 1 and 27% of patients in Group 2 (P = 0.03). These results were encouraging but further investigation is needed.
While another area of the study has been the role of autoimmunity in PPCM, intravenous immunoglobulin (IVIG) as a therapeutic option is less clear. A small, nonrandomized retrospective studied compared six PPCM patients treated with IVIG plus conventional therapy to 11 controls treated with conventional therapy. At 6-month follow-up, the IVIG group showed an improved absolute increase in LVEF (26% vs. 13%) when compared to the controlled group. However, the IMAC Trial (Controlled Trial of Intravenous Immunoglobulin in Recent-Onset Dilated Cardiomyopathy) was not able to reproduce this finding. While both the groups showed significant improvement in LVEF at 6 months, there was no statistically significant difference between the two groups. This trial highlighted the value of conventional therapy (i.e., ACE inhibitors and beta blockers) but failed to show the efficacy of IVIG.
| Prognosis|| |
While there has not been any large prospective trials assessing prognosis in PPCM patients, numerous factors have been identified that may be independent predictors of prognosis. Specifically, echocardiographic findings have yielded the most prognostic information. Factors associated with a favorable prognosis include a small LV diastolic dimension (<5.5–6.0 cm) and elevated systolic function (LVEF >30% and fractional shortening >20%) at the time of diagnosis. Outside of echocardiography, the presence of persistent troponin elevation (>0.04 ng/ml) 2 weeks after the initial presentation with PPCM was found to be associated with persistent LV dysfunction (LVEF ≤50%). Two additional factors associated with lack of recovery of LV function were African-American race and the presence of LV thrombus. Overall, the diagnosis and management including the advent of device therapy have significantly improved overall survival with recent studies showing 5-year survival rates of 90%–95%.,
| Counseling|| |
Numerous studies have shown a high rate of relapse of HF and increases in mortality associated with subsequent pregnancy in the PPCM population. Studies have shown a high rate of recurrence with subsequent pregnancies, specifically in patients with persistent LV dysfunction entering into the next pregnancy.,,, In one study, 57% of patients with prior PPCM and an EF less than 25% had a recurrence of PPCM. Counseling patients with the history of PPCM on the future pregnancies can be extremely difficult and a multidisciplinary approach involving an obstetrician, cardiologist, and pediatrician is recommended. However, despite a paucity of evidence concerning prognosis in PPCM, any patient with persistent LV dysfunction and/or and LVEF ≤25% should be advised against subsequent pregnancies.
| Conclusion|| |
PPCM remains a relatively rare disease though it carries significant morbidity and mortality. PPCM is a diagnosis of exclusion and requires a high index of suspicion given the overlap of signs and symptoms that can be related to a normal pregnancy. Early diagnosis and preservation of LVEF are closely attached to overall prognosis. There have been significant advances in understanding, diagnosis, and management leading to improvement in survival. Novel therapies such as bromocriptine and pentoxifylline show early promise, but large prospective, randomized trials are necessary before these therapies can be widely adopted.
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Conflicts of interest
There are no conflicts of interest.
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