Arrhythmias in Peripartum C a rdi o m y o p a t h y Michael C. Honigberg, MD, MPPa, Michael M. Givertz, MDb,* KEYWORDS Peripartum cardiomyopathy Pregnancy Maternal-fetal health Sudden cardiac death Antiarrhythmic medications Implantable cardioverter-defibrillator Arrhythmias
KEY POINTS Peripartum cardiomyopathy (PPCM) is a complication of late pregnancy and the early postpartum period characterized by dilated cardiomyopathy and heart failure with reduced ejection fraction. Although the prevalence of specific arrhythmias in PPCM is unknown, an estimated 1 in 4 deaths in women with this condition is sudden and presumed secondary to ventricular tachyarrhythmia. Management of PPCM entails standard treatment of heart failure with reduced ejection fraction and prevention of sudden cardiac death (SCD) in patients at increased risk, with special considerations for women who are predelivery or breastfeeding.
INTRODUCTION PPCM is a rare, dilated cardiomyopathy of unknown cause characterized by heart failure with reduced ejection fraction.1 According to the US National Heart, Lung, and Blood Institute, PPCM is diagnosed when a woman develops heart failure in the last month of pregnancy or up to 5 months postpartum, with a left ventricular (LV) ejection fraction less than 45% and no other identifiable cause of heart failure.2 Alternative criteria allowing for earlier and later diagnosis have also been proposed.3 Pregnancy-associated heart failure is a term used to describe women who develop signs and symptoms of heart failure at any time during pregnancy.4
present with symptomatic or even unstable arrhythmias.1,7,8 More common electrocardiographic findings include nonspecific ST-T wave changes, occasionally with conduction abnormalities, such as bundle branch block. Echocardiography shows varying degrees of depressed ventricular systolic function and ventricular dilatation, often with biatrial enlargement as a consequence of valvular regurgitation.5 Chest radiography may show cardiomegaly, pulmonary edema, and/or pleural effusions. Natriuretic peptide levels (eg, B-type natriuretic peptide (BNP) and N-terminal pro-BNP) may be markedly elevated, in contrast with normal pregnancies.9 Low-level troponin elevations also may be seen and predict adverse remodeling.4
Clinical Presentation Epidemiology Well-established risk factors for PPCM include African American race,10 older maternal age (with increased risk above age 30), chronic hypertension,
The authors report no conflicts of interest. a Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; b Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA * Corresponding author. E-mail address: [email protected] Card Electrophysiol Clin - (2015) -–http://dx.doi.org/10.1016/j.ccep.2015.03.010 1877-9182/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
cardiacEP.theclinics.com
In the United States, a majority of women with PPCM are diagnosed in the early postpartum period (Fig. 1).5,6 Patients typically present with heart failure symptoms, although rarely they may
2
Honigberg & Givertz
Fig. 1. Timing of presentation in patients with PPCM in (A) South Africa, (B) Germany, and (C) USA. (From HilfikerKleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nat Rev Cardiol 2014;11(6):365; with permission.)
pregnancy-associated hypertensive conditions (eg, preeclampsia and eclampsia), and multifetal gestation as well as prolonged use of tocolytics in labor.11–13 Hispanic women seem to have the lowest incidence.12 The incidence of PPCM in the United States seems to be increasing (Fig. 2),14 with an average rate of 1 in 968 live births between 2004 and 2011.15 During this period, incidence rose from 8.5 to 11.8 per 10,000 live births.15 Proposed explanations for this trend include climbing rates of advanced maternal age and preeclampsia (secondary to increasing rates of obesity, diabetes, and chronic hypertension), more multifetal gestations due to increased use of assisted reproductive technologies, and growing recognition of PPCM as a disease entity.5,6,15
Approach to Management Standard medical therapies for heart failure are used to manage PPCM, with some exceptions for women who have not yet delivered. For example, diuresis in pregnant women should be
Fig. 2. Temporal trends in incidence rate of PPCM in the United States. (From Kolte D, Khera S, Aronow WS, et al. Temporal trends in incidence and outcomes of peripartum cardiomyopathy in the United States: a nationwide population-based study. J Am Heart Assoc 2014;3(3):e001056; with permission.)
undertaken cautiously to avoid maternal hypotension and uterine hypoperfusion. With respect to afterload reduction, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are teratogenic and are contraindicated in pregnancy. The combination of hydralazine and isosorbide dinitrate may be used instead. b1Selective blockers are preferred to nonselective b-blockers due to risk of uterine stimulation via b2-sympathetic innervation. For pregnant women with severely depressed LV ejection fraction at high risk of thrombus formation, unfractionated heparin and low-molecular-weight heparin are preferred, because warfarin crosses the placenta and may cause fetal hemorrhage.5 For women with acute decompensated heart failure refractory to medical management, mechanical support with an intra-aortic balloon pump, ventricular assist device, or extracorporeal membrane oxygenation may be necessary as a bridge to recovery or transplant.16
Prognosis Recovery of LV function occurs in approximately half of women, although there is considerable variation reported across studies likely due to selection bias. African American race seems to be associated with decreased likelihood of LV recovery.17 A wide range of mortality rates, as high as 20%, has been reported in US series, with most mortality occurring within 6 months of diagnosis.5 A recently published study reported that in-hospital mortality secondary to PPCM in the United States was 1.3%.15 Other major adverse events associated with PPCM are the need for mechanical circulatory support (1.5%), heart transplant (0.5%), and cardiac arrest (2.1%).15 Among women requiring mechanical circulatory support for PPCM, approximately half ultimately require cardiac transplantation; 2-year survival in this group is reported to be 83%.16
Arrhythmias in Peripartum Cardiomyopathy Risk of Subsequent Pregnancy Data suggest that 20% to 50% of women with a history of PPCM experience PPCM recurrence with a subsequent pregnancy.18,19 The risk seems increased among women whose LV ejection fraction failed to normalize after their first episode of PPCM.18,20 Even in women with recovery of resting LV function, there is a small excess risk of recurrent heart failure, although patients demonstrating normal contractile reserve appear to do well.20
ARRHYTHMIAS IN PERIPARTUM CARDIOMYOPATHY Atrial and ventricular arrhythmias are common in patients with heart failure and cardiomyopathy.21 Data on arrhythmia associated specifically with PPCM are sparse, and underlying mechanisms are unclear (Fig. 3). Available data are limited to case reports and small case series, which are summarized in Table 1. In a series of 19 patients in Senegal with PPCM who underwent 24-hour continuous electrocardiographic monitoring, 89% had sinus tachycardia, 37% had premature ventricular contractions, 21% had nonsustained ventricular tachycardia (VT), and 1 patient had first-degree atrioventricular block.22 The exact prevalence of VT and other ventricular arrhythmias in PPCM is unknown.23 In patients presenting with VT, other causes of cardiomyopathy should be considered, including arrhythmogenic right ventricular cardiomyopathy, sarcoidosis, and ischemia/infarction from coronary artery dissection or spasm.
Sudden Cardiac Death A recent study reported that 2.1% of women with PPCM in the United States suffered cardiac arrest in the period 2004 to 2011 (Fig. 4).15 In the same study, the in-hospital mortality rate in women with PPCM was 1.3%. Based on limited data, an estimated 1 in 4 deaths in PPCM is caused by
Hemodynamic load • • • •
Increased heart rate Increased plasma volume Decreased cardiac output Increased SVR
Arrhythmias in peripartum cardiomyopathy
ventricular tachyarrhythmia leading to SCD.24 Some women are only diagnosed with PPCM after presenting with SCD.25 In an American cohort of 100 women with PPCM, 11 subjects died at a mean follow-up of 98 months. Among these patients, 1 had an implantable cardioverterdefibrillator (ICD) but died of heart failure; 2 patients without ICDs died from arrhythmias; and the cause of death was unknown for the other 8 women.17
MANAGEMENT OF ARRHYTHMIA IN PERIPARTUM CARDIOMYOPATHY Medical Management Some women who develop arrhythmias secondary to PPCM may require intravenous antiarrhythmic drugs (AADs) in the acute setting or oral AADs for chronic management. In women requiring AADs prior to delivery, consideration must be given to the effects of AADs on fetal heart rhythm, fetal growth, and uterine activity.23 There is a dearth of data on the risk of AADs to the fetus in pregnancy. As a result, most AADs are Food and Drug Administration (FDA) pregnancy category C (risk cannot be ruled out). Notable exceptions include lidocaine and sotalol, which are FDA category B (no evidence of risk in studies); amiodarone, which is FDA category D (positive evidence of risk, specifically fetal hypothyroidism and prematurity); and dronedarone, which is FDA category X (contraindicated in pregnancy).23,26 Risk categories of AADs are summarized in Table 2. For women requiring treatment of PPCM-associated arrhythmia after delivery, many AADs are compatible with breastfeeding (see Table 2).
External Cardioversion Direct current cardioversion (DCCV) should be performed for patients with unstable arrhythmias Hormonal changes • •
Increased estradiol* Increased progesterone*
•
Increased adrenergic responsiveness*
• •
Fibrosis Inflammation
Autonomic changes
Structural changes
Fig. 3. Potential mechanisms of arrhythmias in PPCM. The asterisk indicates changes occurring during pregnancy. SVR, systemic vascular resistance.
3
4
Honigberg & Givertz
Table 1 Summary of case series and reports documenting specific arrhythmias in peripartum cardiomyopathy Atrial arrhythmias Case Series Biteker et al,35 2012
Study Subjects 42 women in Turkey
Major Finding(s) 5 (11.9%) developed AF
33 women in Senegal 65 women in Nigeria
1 (3%) with AF; 1 (3%) with MAT 2 (3.1%) developed AF
Study Subjects 45 women in Pakistan
Major Finding(s) 3 (6.6%) had VT at presentation
Diao et al,22 2004 Case reports Tokuda et al,30 2013
19 women in Senegal Patient 38-year-old woman with PPCM presented with sustained VT
Puri et al,7 2009
25-year-old woman at 36 wk gestation found to have VT 30-year-old woman at 38 wk gestation (asymptomatic) found to have VT
4 (21%) had NSVT Comments Patient with known PPCM and LV ejection fraction 20%; ICD placed 1 y before presentation for monomorphic VT. Mapping revealed low-voltage epicardial scar that was ablated with resolution of VT. Echocardiography revealed depressed LV ejection fraction leading to diagnosis of PPCM. Echocardiography revealed depressed LV ejection fraction leading to diagnosis of PPCM.
Kane et al,36 2010 Isezuo and Abubakar,37 2007 Ventricular tachycardia Case Series Laghari et al,38 2013
Gemici et al,8 2004
Comments No apparent effect of AF on survival or recovery of LV function
Comments No further description of arrhythmias provided
Palma et al,39 2001 Ventricular fibrillation Case Series Duncker et al,33 2014
Case report Nelson et al,40 2012 Colombo et al,41 2002
Hetey et al,42 1996 Pearl,43 1995
33-year-old woman with PPCM presenting with incessant VT
Patient underwent VT ablation that was transiently successful before VT recurred, leading to hemodynamic collapse and death.
Study Subjects 12 women in Germany with PPCM: 9 with LV ejection fraction
KEY POINTS Peripartum cardiomyopathy (PPCM) is a complication of late pregnancy and the early postpartum period characterized by dilated cardiomyopathy and heart failure with reduced ejection fraction. Although the prevalence of specific arrhythmias in PPCM is unknown, an estimated 1 in 4 deaths in women with this condition is sudden and presumed secondary to ventricular tachyarrhythmia. Management of PPCM entails standard treatment of heart failure with reduced ejection fraction and prevention of sudden cardiac death (SCD) in patients at increased risk, with special considerations for women who are predelivery or breastfeeding.
INTRODUCTION PPCM is a rare, dilated cardiomyopathy of unknown cause characterized by heart failure with reduced ejection fraction.1 According to the US National Heart, Lung, and Blood Institute, PPCM is diagnosed when a woman develops heart failure in the last month of pregnancy or up to 5 months postpartum, with a left ventricular (LV) ejection fraction less than 45% and no other identifiable cause of heart failure.2 Alternative criteria allowing for earlier and later diagnosis have also been proposed.3 Pregnancy-associated heart failure is a term used to describe women who develop signs and symptoms of heart failure at any time during pregnancy.4
present with symptomatic or even unstable arrhythmias.1,7,8 More common electrocardiographic findings include nonspecific ST-T wave changes, occasionally with conduction abnormalities, such as bundle branch block. Echocardiography shows varying degrees of depressed ventricular systolic function and ventricular dilatation, often with biatrial enlargement as a consequence of valvular regurgitation.5 Chest radiography may show cardiomegaly, pulmonary edema, and/or pleural effusions. Natriuretic peptide levels (eg, B-type natriuretic peptide (BNP) and N-terminal pro-BNP) may be markedly elevated, in contrast with normal pregnancies.9 Low-level troponin elevations also may be seen and predict adverse remodeling.4
Clinical Presentation Epidemiology Well-established risk factors for PPCM include African American race,10 older maternal age (with increased risk above age 30), chronic hypertension,
The authors report no conflicts of interest. a Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; b Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA * Corresponding author. E-mail address: [email protected] Card Electrophysiol Clin - (2015) -–http://dx.doi.org/10.1016/j.ccep.2015.03.010 1877-9182/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
cardiacEP.theclinics.com
In the United States, a majority of women with PPCM are diagnosed in the early postpartum period (Fig. 1).5,6 Patients typically present with heart failure symptoms, although rarely they may
2
Honigberg & Givertz
Fig. 1. Timing of presentation in patients with PPCM in (A) South Africa, (B) Germany, and (C) USA. (From HilfikerKleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nat Rev Cardiol 2014;11(6):365; with permission.)
pregnancy-associated hypertensive conditions (eg, preeclampsia and eclampsia), and multifetal gestation as well as prolonged use of tocolytics in labor.11–13 Hispanic women seem to have the lowest incidence.12 The incidence of PPCM in the United States seems to be increasing (Fig. 2),14 with an average rate of 1 in 968 live births between 2004 and 2011.15 During this period, incidence rose from 8.5 to 11.8 per 10,000 live births.15 Proposed explanations for this trend include climbing rates of advanced maternal age and preeclampsia (secondary to increasing rates of obesity, diabetes, and chronic hypertension), more multifetal gestations due to increased use of assisted reproductive technologies, and growing recognition of PPCM as a disease entity.5,6,15
Approach to Management Standard medical therapies for heart failure are used to manage PPCM, with some exceptions for women who have not yet delivered. For example, diuresis in pregnant women should be
Fig. 2. Temporal trends in incidence rate of PPCM in the United States. (From Kolte D, Khera S, Aronow WS, et al. Temporal trends in incidence and outcomes of peripartum cardiomyopathy in the United States: a nationwide population-based study. J Am Heart Assoc 2014;3(3):e001056; with permission.)
undertaken cautiously to avoid maternal hypotension and uterine hypoperfusion. With respect to afterload reduction, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are teratogenic and are contraindicated in pregnancy. The combination of hydralazine and isosorbide dinitrate may be used instead. b1Selective blockers are preferred to nonselective b-blockers due to risk of uterine stimulation via b2-sympathetic innervation. For pregnant women with severely depressed LV ejection fraction at high risk of thrombus formation, unfractionated heparin and low-molecular-weight heparin are preferred, because warfarin crosses the placenta and may cause fetal hemorrhage.5 For women with acute decompensated heart failure refractory to medical management, mechanical support with an intra-aortic balloon pump, ventricular assist device, or extracorporeal membrane oxygenation may be necessary as a bridge to recovery or transplant.16
Prognosis Recovery of LV function occurs in approximately half of women, although there is considerable variation reported across studies likely due to selection bias. African American race seems to be associated with decreased likelihood of LV recovery.17 A wide range of mortality rates, as high as 20%, has been reported in US series, with most mortality occurring within 6 months of diagnosis.5 A recently published study reported that in-hospital mortality secondary to PPCM in the United States was 1.3%.15 Other major adverse events associated with PPCM are the need for mechanical circulatory support (1.5%), heart transplant (0.5%), and cardiac arrest (2.1%).15 Among women requiring mechanical circulatory support for PPCM, approximately half ultimately require cardiac transplantation; 2-year survival in this group is reported to be 83%.16
Arrhythmias in Peripartum Cardiomyopathy Risk of Subsequent Pregnancy Data suggest that 20% to 50% of women with a history of PPCM experience PPCM recurrence with a subsequent pregnancy.18,19 The risk seems increased among women whose LV ejection fraction failed to normalize after their first episode of PPCM.18,20 Even in women with recovery of resting LV function, there is a small excess risk of recurrent heart failure, although patients demonstrating normal contractile reserve appear to do well.20
ARRHYTHMIAS IN PERIPARTUM CARDIOMYOPATHY Atrial and ventricular arrhythmias are common in patients with heart failure and cardiomyopathy.21 Data on arrhythmia associated specifically with PPCM are sparse, and underlying mechanisms are unclear (Fig. 3). Available data are limited to case reports and small case series, which are summarized in Table 1. In a series of 19 patients in Senegal with PPCM who underwent 24-hour continuous electrocardiographic monitoring, 89% had sinus tachycardia, 37% had premature ventricular contractions, 21% had nonsustained ventricular tachycardia (VT), and 1 patient had first-degree atrioventricular block.22 The exact prevalence of VT and other ventricular arrhythmias in PPCM is unknown.23 In patients presenting with VT, other causes of cardiomyopathy should be considered, including arrhythmogenic right ventricular cardiomyopathy, sarcoidosis, and ischemia/infarction from coronary artery dissection or spasm.
Sudden Cardiac Death A recent study reported that 2.1% of women with PPCM in the United States suffered cardiac arrest in the period 2004 to 2011 (Fig. 4).15 In the same study, the in-hospital mortality rate in women with PPCM was 1.3%. Based on limited data, an estimated 1 in 4 deaths in PPCM is caused by
Hemodynamic load • • • •
Increased heart rate Increased plasma volume Decreased cardiac output Increased SVR
Arrhythmias in peripartum cardiomyopathy
ventricular tachyarrhythmia leading to SCD.24 Some women are only diagnosed with PPCM after presenting with SCD.25 In an American cohort of 100 women with PPCM, 11 subjects died at a mean follow-up of 98 months. Among these patients, 1 had an implantable cardioverterdefibrillator (ICD) but died of heart failure; 2 patients without ICDs died from arrhythmias; and the cause of death was unknown for the other 8 women.17
MANAGEMENT OF ARRHYTHMIA IN PERIPARTUM CARDIOMYOPATHY Medical Management Some women who develop arrhythmias secondary to PPCM may require intravenous antiarrhythmic drugs (AADs) in the acute setting or oral AADs for chronic management. In women requiring AADs prior to delivery, consideration must be given to the effects of AADs on fetal heart rhythm, fetal growth, and uterine activity.23 There is a dearth of data on the risk of AADs to the fetus in pregnancy. As a result, most AADs are Food and Drug Administration (FDA) pregnancy category C (risk cannot be ruled out). Notable exceptions include lidocaine and sotalol, which are FDA category B (no evidence of risk in studies); amiodarone, which is FDA category D (positive evidence of risk, specifically fetal hypothyroidism and prematurity); and dronedarone, which is FDA category X (contraindicated in pregnancy).23,26 Risk categories of AADs are summarized in Table 2. For women requiring treatment of PPCM-associated arrhythmia after delivery, many AADs are compatible with breastfeeding (see Table 2).
External Cardioversion Direct current cardioversion (DCCV) should be performed for patients with unstable arrhythmias Hormonal changes • •
Increased estradiol* Increased progesterone*
•
Increased adrenergic responsiveness*
• •
Fibrosis Inflammation
Autonomic changes
Structural changes
Fig. 3. Potential mechanisms of arrhythmias in PPCM. The asterisk indicates changes occurring during pregnancy. SVR, systemic vascular resistance.
3
4
Honigberg & Givertz
Table 1 Summary of case series and reports documenting specific arrhythmias in peripartum cardiomyopathy Atrial arrhythmias Case Series Biteker et al,35 2012
Study Subjects 42 women in Turkey
Major Finding(s) 5 (11.9%) developed AF
33 women in Senegal 65 women in Nigeria
1 (3%) with AF; 1 (3%) with MAT 2 (3.1%) developed AF
Study Subjects 45 women in Pakistan
Major Finding(s) 3 (6.6%) had VT at presentation
Diao et al,22 2004 Case reports Tokuda et al,30 2013
19 women in Senegal Patient 38-year-old woman with PPCM presented with sustained VT
Puri et al,7 2009
25-year-old woman at 36 wk gestation found to have VT 30-year-old woman at 38 wk gestation (asymptomatic) found to have VT
4 (21%) had NSVT Comments Patient with known PPCM and LV ejection fraction 20%; ICD placed 1 y before presentation for monomorphic VT. Mapping revealed low-voltage epicardial scar that was ablated with resolution of VT. Echocardiography revealed depressed LV ejection fraction leading to diagnosis of PPCM. Echocardiography revealed depressed LV ejection fraction leading to diagnosis of PPCM.
Kane et al,36 2010 Isezuo and Abubakar,37 2007 Ventricular tachycardia Case Series Laghari et al,38 2013
Gemici et al,8 2004
Comments No apparent effect of AF on survival or recovery of LV function
Comments No further description of arrhythmias provided
Palma et al,39 2001 Ventricular fibrillation Case Series Duncker et al,33 2014
Case report Nelson et al,40 2012 Colombo et al,41 2002
Hetey et al,42 1996 Pearl,43 1995
33-year-old woman with PPCM presenting with incessant VT
Patient underwent VT ablation that was transiently successful before VT recurred, leading to hemodynamic collapse and death.
Study Subjects 12 women in Germany with PPCM: 9 with LV ejection fraction
