Peripartum and Postpartum cardiomyopathy - Etiopathogenesis, Clinical features, Advances in Management

Peripartum and Postpartum cardiomyopathy - Etiopathogenesis, Clinical features, Advances in Management

1. PERIPARTUM CARDIOMYOPATHY Chairperson ; Dr Ram S Kaulgud Student ;Dr Ibin Shah

2. Introduction Peripartum cardiomyopathy (PPCM) is a type of dilated cardiomyopathy of unknown origin It occurs in previously healthy women in the final month of pregnancy and up to 5 months after delivery 1 The incidence —less than 0.1% of pregnancies— Morbidity and mortality rates are ranging from 5% to 7%. 2 For some women, the clinical and echocardiographic status improve and may return to normal, whereas for others, PPCM progresses to cardiac failure and even sudden cardiac death. 1. Pearson G,et al . JAMA. 2010;283(9):1183-1188. 2.. Denise Hilfiker-Kleiner et al European Heart Journal 2015 ;186(5):564-572

3. Definitions European Society of Cardiology Working Group, “an idiopathic cardiomyopathy presenting with heart failure secondary to LV systolic dysfunction towards the end of pregnancy or in the months following delivery when no other cause of heart failure is found. The LV may not be dilated but the ejection Fraction is nearly always below 45%.” 1 3. Sliwa K, Hilfiker-Kleiner D, Petrie MC, et al: Eur J Heart Fail 12:767, 2010.

4. The National Heart Lung and Blood Institute definition 1 All 4 of the following: Classic 1. Development of cardiac failure in the last month of pregnancy or within 5 months postpartum 2. No identifiable cause for the cardiac failure 3. No recognizable heart disease before the last month of Pregnancy Additional 1. Strict echocardiographic indication of left ventricular dysfunction: a. Ejection fraction <45% and/or b. Fractional shortening <30% c. End-diastolic dimension >2.7 cm/m2 1 Pearson G, Veille J, Rahimtoola S, et al.. JAMA. 2010;283(9):1183-1188 .

5. EPIDEMIOLOGY Reported incidence varies because diagnosis is not consistent, difference in reporting pattern, geographical difference and echo availability Incidence in india ( 1 in 1374) 4 Reported incidence in Haiti is 1 in 300, and 1 in 4000 live births in the US 4. Pandit V, Shetty S, Kumar A et al; Incidence and out come of peripartum Cardiomyopathy from a tertiary hospital in South India. Trop Doct 2009;39:168-9.

6. Risk factors upper and lower extremes of age Multiparity Mulitple pregnancy Pregnancy complicated by preeclampsia and gestational hypertension Maternal cocaine and alcohol abuse African American ethnicity Use of medications to prevent premature labour 5 Peripartum Cardiomyopathy Michael M. Givertz , MD Circulation. 2013;127:e622-e626

7. ETIOLOGY 1 Precise mechanism not yet identified Many suggested etiologies include: Excessive prolactin excretion Viral mayocarditis Abnormal immune response to pregnancy Maladaptive response to hemodynamic changes in pregnancy Stress activated cytokines Prolonged tocolytics 6. PERIPARTUMCARDIOMYOPATHY:REVIEW AND PRACTICEGUIDELINES . AJCC􀀀AMERICAN JOURNAL OF CRITICAL CARE, March 2012, Volume 21, No. 2

8. Genetic factors similar to dialated cardiomyopathy also suggested, although not yet proven The European Society of Cardiology currently classifies PPCM as a nonfamilial , nongenetic form of dilated cardiomyopathy .

9. ETIOLOGY- Prolactin 1 Elevated prolactin is associated with increased blood volume and decreased blood pressure Women with PPCM had low levels of STAT3 protein in heart This leads to elevated levels of activated cathepsin D, which in turn increases 16-kD prolactin levels. The 16-kDa derivative exhibit antiangiogenic, proapoptotic, proinflammatory, and cardiotoxic properties 7.Hilfiker-et al . Cell. 2014;128(3):589-600.

10. Etiology- viral myocarditis 1 Many studies revealed myocarditis on endomyocardial biopsy- dense lymphocytic infiltration with a variable amount of myocytic edema , necrosis, and fibrosis however, clinical outcomes did not differ between women with and without evidence of myocarditis on biopsy. Parvovirus B19 , Human Herpes Virus , Ebstein Baar virus and Cytomegalovirus 8. Melvin KR et al. N Engl J Med. 2013;307(12):731-734 . 9. .Midei MG et al. Circulation. 2010;81:922-928.

11. ETIOLOGY- Abnormal immune response 1 During pregnancy fetal cells released into the maternal bloodstream are not rejected by the mother because of the natural immunosuppresion that occurs during pregnancy However, after delivery, the immunity returns to normal Pathological autoimmune response develops to fetal cells in cardiac tissue can occur, leading to PPCM in the mother after birth 10.Ansari AA et al . Clin Rev Allergy Immunol. 2012;23:301-324.

12. The timing of presentation in the immediate postpartum period support autoimmune pathogenesis

13. ETIOLOGY- Abnormal hemodynamic response 1 During pregnancy, blood volume and cardiac output increase and afterload decreases because of relaxation of vascular smooth muscle These changes cause a brief, and reversible, hypertrophy of the left ventricle to meet the needs of the mother and fetus 1.Pearson G et al. JAMA. 2010;283(9):1183-1188.

14. This transient left ventricular dysfunction during the third trimester and early postpartum period resolves shortly after birth in a normal pregnancy An exaggerated decrease in left ventricular function when these hemodynamic changes of pregnancy occur can lead to PPCM

15. ETIOLOGY- Apoptosis and Inflammation 1 An increased concentration of cytokines like tumor necrosis factor a C-reactive protein Higher levels of Fas/Apo-1, a plasma marker for apoptosis have been identified in women with PPCM, than in healthy volunteers Fas/Apo -1 levels were also higher among those who died of PPCM than those who survived 11.Sliwa et al. J Am Coll Cardiol . 2011;35(3):701-705.

16. ETIOLOGY- selenium and malnutrition 1 Deficiencies of selenium increase cardiovascular susceptibility to viral infections, hypertension, and hypocalcemia Selenium level less than 70ug/l was found significant 12. Kamilu M. Karaye 1,2,*, Isah A. Yahaya et al Int. J. Mol. Sci. 2015, 16, 7644-7654;

17. ETIOLOGY- Prolonged tocolytics 1 Prolonged tocolysis refers to the use of tocolytic agents (b-sympathomimetic drugs) for more than 4 weeks- ritodrine,terbutaline Tocolytic agents act via beta-1 and beta-2 adrenergic receptors, thereby resulting in tachycardia, fluid retention, hypokalemia , and hyperglycemia . A study has revealed the occurrence of pulmonary edema in pregnant women following the use tocolytics Persistent tachycardia secondary to ritodrine might result in transient myocardial ischemia as well 13 Garg et al.Cardiology in Review • Volume 23, Number 2, March/April 2015

18. Genetics 1 Genes implicated are - MYH7 , SCN5A,TNNT2 ,MYBPC3 14.BRAUNWALD’S HEART DISEASE A TEXTBOOK OF CARDIOVASCULAR MEDICINE 10 th edition

19. Clinical manifestations and diagnosis Features of normal pregnancy include Increased blood volume Increased metabolic requirements relative anemia Changes in vascular resistance Mild ventricular dialatation Increased cardiac output Hence features of PPCM may easily be masked or missed

20. Symptoms Shortness of breath Fatigue Leg swelling Abdominal pain ,bloating Weight gain Cough,chest pain Palpitations

21. Signs Tachycardia Blood pressure is often normal or decreased Hypoxia jugular venous distention S3 and S4 gallop Rales, pleural effusion Hepatomegaly

22. Women can also have Arrhythmias - atrial fibrillation, atrial flutter, and ventricular tachycardia 1 embolic events due to the dilated, dysfunctional left ventricle acute myocardial infarction due to decreased perfusion to the coronary arteries 15 Michael C. Honigberg , , et al June 2015 Volume 7, Issue 2, Pages 309–317 cardiac electrophysiology clinic

23. Diagnosis Definitive diagnosis of PPCM depends on echocardiographic identification of new-onset heart failure during a limited period around parturition. PPCM is a diagnosis of exclusion as per its definition given in 2010 by European Society of Cardiology Working Group on Peripartum Cardiomyopathy PPCM is defined as an idiopathic cardiomyopathy manifested as heart failure due to left ventricular systolic dysfunction toward the end of pregnancy or in the months after delivery when no other cause of heart failure is found

24. A diagnosis of PPCM requires the exclusion of other causes of heart failure: myocardial infarction Sepsis severe preeclampsia pulmonary embolism valvular diseases other forms of cardiomyopathy

25. DIAGNOSTIC CRITERIA FOR PERIPARTRUM CARDIOMYOPATHY All 4 of the following: Classic 1. Development of cardiac failure in the last month of pregnancy or within 5 months postpartum 2. No identifiable cause for the cardiac failure 3. No recognizable heart disease before the last month of Pregnancy Additional 1. Strict echocardiographic indication of left ventricular dysfunction: a. Ejection fraction <45% and/or b. Fractional shortening <30% c. End-diastolic dimension >2.7 cm/m2

26. NO- consider other causes YES- Meets criteria for diagnosis for peripartum cardiomyopathy Consultation with cardiologist, obstetrician, perinatologist If diagnosis is made before the woman gives birth: involve anesthesiology and neonatology also, and consider transfer to a high-risk perinatal center

27. INVESTIGATIONS

28. ECHO Findings in women with PPCM are consistent with the findings in heart failure decreased ejection fraction global dilatation thinned-out cardiac walls Increased LV mass Diffuse LV hypokinesis

29. echocardiography is non invasive and allows serial evaluations in pregnant women Serial echocardiography with Doppler imaging is used to evaluate and monitor regional and global left and right ventricular function, valvular structure and function, possible pericardial pathological changes, and mechanical complications

30. CHEST XRAY Radiological evidence of heart failure: Cardiomegaly pulmonary congestion pleural effusions However, diagnosing cardiomegaly on the basis of a chest radiograph in a pregnant patient is difficult because the heart is pushed upward and laterally, giving the false impression of cardiomegaly

31. ECG May be normal or may show: left ventricular hypertrophy ST-T wave abnormalities Dysrhythmias Q-waves in the anteroseptal precordial leads prolonged PR and QRS intervals

32. OTHER INVESTIGATIONS complete blood cell counts troponin elevation (≥0.04 ng/mL) within 2 weeks of PPCM onset is a poor predictor of LV systolic dysfunction B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide can help in confirming the diagnosis in such situations S.urea and S.creatinine S.electrolytes Liver function tests thyroid-stimulating hormone 16.Li W et al Can J Cardiol . 2016 Mar;32(3):362-8 17.Forster O, Hilfiker-Kleiner et al . Eur J Heart Fail. 2012;10:861–868

33. CARDIAC MRI cardiac MRI helps in the accurate assessment of chamber volume and ventricular function ,LV thrombus and myocardial fibrosis in patients with PPCM as compared with echocardiography can help in characterizing the pathogenesis of the disease can be used to distinguish inflammatory from noninflammatory pathogenesis- 18.Baruteau AE, , et al. . Int J Cardiol . 2010;144(1):143-145.

34. MANAGEMENT

35. Management of PPCM is similar to standard treatment for other forms of heart failure careful attention should be paid to fetal safety and to excretion of drug or drug metabolites during breastfeeding after delivery Treatment focuses on reducing preload and afterload and increasing cardiac inotropy . Medications should be continued till left ventricular dysfunction is improved or resolved Women with PPCM should be treated in the hospital when they have evidence of hypotension, worsening heart failure, altered mental status, and increased work of breathing

36. COMPENSATED HEART FAILURE PRELOAD REDUCTION Achieved by the use of vasodialators Nitrates- safe during pregnanacy Loop diuretics- use with caution as it can produce rapid intravascular volume changes in antepartum women- may be harmful to fetus Restriction of dietary sodium Bed rest- no longer recommended- increased risk of thromboembolism Light exercise recommended

37. monitoring Pulse oximetry Cardiac monitoring is required..ST segment monitoring Non invasive BP monitoring Fetal heart rate monitoring- compromise in mothers hemodynamic status and oxygenation can bring about fetal distress Optimising these parameters can resolve fetal distress and reduce need for emergency caesarean section

38. Standard Medical Therapy The treatment of heart failure in pregnant females is analogous to the management of other types of heart failure Pre delivery diuretics Beta blockers Hydralazine and nitrates Anti coagulation 19.Jackson AM, et al. Heart 2017

39. Post delivery 1. conventional medical therapy - diuretics ,ACE Inhibitors, ARBs ,MRA ,beta blockers 2. low molecular weight heparin or warfarin 3. Follow up 4. counselling regarding contraception 5 counselling regarding subsequent pregnancy 19.Jackson AM, et al. Heart 2017

40. Long term management In case of persisiting LV dysfunction consider ICD In case of myocardial recovery consider withdrawal of treatment

41. Diuretics Furosemide reduces preload and improves pulmonary vascular congestion and peripheral edema . monitor the patient’s volume status, as diuretic-induced dehydration can result in oligohydroamnios,decreased uterine perfusion, and subsequent worsening of maternal metabolic acidosis. 13.Garg et al 2014 Wolters Kluwer Health, Cardiology in Review • Volume 23, Number 2, March/April 2015

42. Both loop and thiazide diuretics are relatively safe during pregnancy (category C and category B, respectively). Despite its excretion in breast milk, no case of furosemide toxicity in infants have been reported to date, therefore it is considered compatible with breast-feeding.

43. Spironolactone its role and use in PPCM is controversial because of its teratogenic and antiandrogenic effects reported in male rat models no teratogenicity has been reported in humans Spironolactone is currently approved by the American Academy of Pediatrics for management of heart failure in the postpartum period.

44. ACE inhibitors and angiotensin receptor blockers (ARBs) contraindicated in pregnant patients with PPCM Highly teratogenic both during pregnancy and lactation

45. The teratogenic effects of ACE inhibitors and ARBs include oligohydroamnios , intrauterine growth retardation limb contractures, patent ductus arteriosus, Hypocalvaria fetal renal failure,

46. According to the American Academy of Pediatrics , enalapril and captopril can be safely administered during lactation

47. Digoxin- to be used in those with left ventricular systolic dysfunction with ejection fraction <40% while receiving standard therapy…safe in pregnanacy Digoxin levels between 0.5 and 0.8 ng/mL were beneficial and levels of 1.1–1.5 ng/mL were associated with increased mortality 20.The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 2009;336:525–533.

48. Nitrates and hydralazine They are relatively safe during pregnancy and serve as an effective combination for afterload reduction. 4.Sliwa K, Hilfiker-Kleiner D,et alEur J Heart Fail. 2010;12:767–778.

49. Beta blockers Metoprolol, carvedilol, and bisoprolol (category C) have been shown to reduce the risk of ventricular arrhythmias, sudden cardiac death, and mortality. Selective beta blockers are preferred to avoid antitocolytic effect Metoprolol tartrate is the most common beta-blocker used in pregnancy 21.Easterling TR et al Obstet Gynecol. 2010;98:427–433.

50. The circulating levels of TNF-α decreases after treatment with metoprolol or bisoprolol Decrease in myocardial expression, and production of TNF-α when treated with beta-blockers provides positive outcomes in patients with cardiomyopathy According to the American Academy of Pediatrics , metoprolol tartrate is compatible during lactation, but it is essential to monitor the growth curve in the neonate

51. Duration of medical therapy

52. Anticoagulation LV dysfunction is associated with a 1–2.5 per 100 patient years increased risk of thromboembolic events Indications intracardiac thrombus evidence of systemic embolism heart failure and paroxysmal or persistent AF 22.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

53. Warfarin is probably safe during the first 6 weeks of gestation, but there is a risk of embryopathy if warfarin is taken between 6 and 12 weeks of gestation Unfractionated heparin is usually the preferred agent because of its shorter half-life and it is easily reversible in an event of urgent/emergent delivery

54. Defibrillators Patients with persistently reduced EF (<35% with New York Heart Association class II, III for longer than 3 months on medical therapy) should be considered for implantation of defibrillators for primary prevention of sudden cardiac death based on standard criteria.

55. Cardiac resynchronization therapy In patients with electrical dyssynchrony manifested by wide QRS duration (150 ms ) with left bundle branch morphology

56. Mechanical Assist Device and Heart Transplantation LVAD can serve as a bridge to transplant or to recovery 1.Patients with PPCMwho fail to recover their LV systolic function between 3 and 6 months postpartum. 2. In critically ill patients with PPCM who are inotrope-dependent,

57. EXPERIMENTAL THERAPY Bromocriptine Dopamine receptor agonist Reduced secretion of prolactin from the anterior pituitary Facilitate ventricular recovery in PPCM Dosing- 2.5 mg two times a day for 2 weeks, followed by 2.5 mg once daily for 6 weeks 23.Habedank D, et al . Eur J Heart Fail. 2012;10:1149–1151 .

58. Adverse effects -increased thrombotic events including myocardial infarction, strokes, seizures, and retinal vein occlusion Inhibits breast milk production, thereby depriving the mothers and newborns from the emotional and physical benefits of breast-feeding

59. Pentoxifylline xanthine derivative Inhibits the production of TNF-α and inhibit apoptosis Dose -400 mg three times a day for 6 months

60. Low-sodium diet: limit of 2 g sodium per day Fluid restriction: 2 L/day Daily weight monitoring, adequate blood pressure control Light daily activity: if tolerated ( eg , walking) Non pharmaceutical therapies

61. MANAGEMENT OF DECCCOMPENSATED HEART FAILURE IN PERIPARTUM CARDIOMYOPATHY IN SHORT Airway Intubate promptly upon distress for increased work of breathing to prevent complications with difficult airway later in treatment Breathing Provide supplemental oxygen Maintain continuous pulse oximetry to monitor SaO2 Measure arterial blood gases (if available) every 4-6 h until breathing is stable Circulation Start cardiac and blood pressure monitoring Obtain central venous access with central venous pressure monitoring In antepartum women, obtain fetal monitoring

62. DIURETIC i.v. furosemide is the most commonly used first-line diuretic. The dose should be limited to the smallest amount to provide adequate clinical effect and modified according to renal function Initially i.v. boluses of 20–40 mg are administered 22.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure European Heart Journal (2016) 37, 2129–2200

63. Vasodilators Nitroglycerine Start with10–20 μg /min, increase up to 200 μg /min Side effects: Hypotension, headache, Tolerance on continuous use Isosorbide dinitrate Start with 1 mg/h, increase up to 10 mg/h Side effects : Hypotension, headache Tolerance on continuous use

64. Nitroprusside Start with 0.3 μg /kg/min and increase up to 5 μg /kg/min Adverse effect :Hypotension, isocyanate toxicity Cyanide toxicity can develop within 1 hr with infusions >10 mcg/kg/min These drugs should be avoided if SBP <90 mm hg

65. Positive inotropes Dobutamine 2–20 μg/kg/min Dopamine 5–10 μ g/kg/min Norepinephrine 0.2–1.0 μg/kg/min Use of an inotrope should be reserved for patients with a severe reduction in cardiac output resulting in compromised vital organ perfusion, which occurs most often in hypotensive AHF.

66. Delivery 1 Vaginal delivery is always preferable if the patient is haemodynamically stable and there are no obstetric indications for caesarean delivery. Urgent delivery irrespective of gestation duration should be considered in women with advanced heart failure and haemodynamic instability despite treatment. 22. ESC Guidelines 2016

67. PROGNOSIS Prognosis is positively related to recovery of ventricular function Failure of heart size to return to normal is associated with increased mortality and morbidity A fractional shortening less than 20% and a left ventricular diastolic dimension of 6 cm or greater at the time of diagnosis are associated with a more than 3-fold higher risk for persistent cardiac dysfunction 1 ejection fraction was the strongest predictor of outcome in women with PPCM. EF < 25% is associated with poor otcome 30-50% of women with PPCM recover baseline LV function in 6 months 23.Chapa JB, et al. Prognostic value of echocardiography in peripartum cardiomyopathy.Obstet Gynecol 2011;105:1303–8.

68. Reported mortality rates vary from 1.36% to 15% in another studies Although rates have improved, mortality remains extremely high in women with PPCM.

69. Subsequent pregnancies Another major concern is regarding subsequent pregnancies for those who had survived PPCM No established recommendations exist Recovery of LV function determines survival in subsequent pregnancies Women with persistent heart failure should be advised against future pregnancies 1 24.Uri Elkayam , MD JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO. 15, 2014

70. Subsequent pregnancies can increase the risk for recurrent episodes of PPCM, irreversible cardiac damage and decreased left ventricular function, worsening of a woman’s clinical condition, and even death Even in those with recovered LV function, the left ventricular contractile reserve may remain impaired, and recurrence of PPCM is still possible

71. Follow up Follow up with echocardiogram at regular intervals ,at the time of discharge, 6 weeks, 6 months, and annually subsequently

72. CONCLUSION PPCM is a type of dialated cardiomyopathy that affects previously healthy women in the final month of pregnancy and up to 5 months after delivery Disease has multifactorial origin and no single explanation of pathogenesis is established For some women, the clinical and echocardiographic status improve rapidly and sometimes return to normal. In other women, the clinical condition rapidly worsens, no improvement occurs with medical therapy, and chronic heart failure from persistent ventricular dysfunction develops.

73. Those who recover from left ventricular dysfunction may be at risk for recurrence of heart failure and death in subsequent pregnancies Careful assessment of risk factors in pregnant women could help in the prevention of PPCM Tools to stratify women by risk who have recovered from PPCM are needed to predict the risk of future pregnancies

74. References Pearson G, Veille J, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA. 2010;283(9):1183-1188. Denise Hilfiker-Kleiner*, Arash Haghikia , Justus Nonhoff , and Johann Bauersachs . Peripartum cardiomyopathy: current management and future perspectives. European Heart Journal Advance Access published January 29, 2015 Sliwa K, Hilfiker-Kleiner D,et al Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of CardiologyWorking Group on peripartum cardiomyopathy. Eur J Heart Fail 2010;12:767–778

75. 4. Pandit V, Shetty S, Kumar A et al; Incidence and out come of peripartum Cardiomyopathy from a tertiary hospitalin South India. Trop Doct 2009;39:168-9. 5. Peripartum Cardiomyopathy Michael M. Givertz , MD Circulation. 2013;127:e622-e626 6. PERIPARTUMCARDIOMYOPATHY:REVIEW AND PRACTICEGUIDELINES . AJCC􀀀AMERICAN JOURNAL OF CRITICAL CARE, March 2012, Volume 21, No. 2 7. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell . 2014;128:589–600.

76. 8. Melvin KR et al. N Engl J Med. 2013;307(12):731-734. 9. . Midei MG, DeMent SH, Feldman AM, et al. Peripartum myocarditis and cardiomyopathy. Circulation . 2010;81:922–928. 10.Ansari AA, Fett JD, Carraway RE, et al. Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol . 2012;23:301–324. 11.Sliwa K, Skudicky D, Bergemann A, et al. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas /APO-1. J Am Coll Cardiol . 2000;35:701–705.

77. 12.Serum Selenium and Ceruloplasmin in Nigerians with Peripartum Cardiomyopathy Kamilu M. Karaye 1,2,*, Isah A. Yahaya Int. J. Mol. Sci. 2015 , 16 , 7644-7654 13 Garg et al peripartum cardiomayopathy Cardiology in Review • Volume 23, Number 2, March/April 2015 14 BRAUNWALD’S HEART DISEASE A TEXTBOOK OF CARDIOVASCULAR MEDICINE 10 th edition 15 Michael C. Honigberg , , et al June 2015 Volume 7, Issue 2, Pages 309–317 cardiac electrophysiology clinic

78. 16.Li W et al Clinical Characteristics and Long-term Predictors of Persistent Left Ventricular Systolic Dysfunction in Peripartum Cardiomyopath Can J Cardiol . 2016 Mar;32(3):362-8 17. Karen Sliwa , Olaf Förster , et al Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients Eur J Heart Fail. 2012;10:861–868

79. 18.Baruteau AE, , et al. . Int J Cardiol . 2010;144(1):143-145. 19 Peripartum cardiomyopathy: diagnosis and management Alice M Jackson, Heart Online First, published on November 9, 2017 20.The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 2009;336:525–533. 21.Easterling TR, Carr DB, Brateng D, et al. Treatment of hypertension in pregnancy: effect of atenolol on maternal disease, preterm delivery, and fetal growth. Obstet Gynecol . 2011;98:427–433. 22.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

80. 23.Chapa JB, et al. Prognostic value of echocardiography in peripartum cardiomyopathy.Obstet Gynecol 2011;105:1303–8 . 24. Uri Elkayam , MD JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO. 15, 2014