PERI-PARTUM CARDIOMYOPATHY:

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1 PERI-PARTUM CARDIOMYOPATHY: Recent insights in its patho-physiology and treatment DR.AN PATNAIK

2 [Heart Failure Association of the European Society of Cardiology Working Group on PPCM 2010] Eur J Heart Fail. Aug 2010;12(8): WCC&IVUS2015 DEFINITIONS PERIPARTUM: the last month of gestation or the first few months after delivery, with reference to the mother CARDIOMYOPATHY: chronic disease of the myocardium in which it is abnormally enlarged, thicken ed, and/or stiffened affecting ventricular function PERIPARTUM CARDIOMYOPATHY: an idiopathic cardiomyopathy that presents with heart failure secondary to left ventricular systolic dysfunction toward the end of pregnancy or in the months after delivery, in the absence of any other cause of heart failure

3 HIGH-LIGHTS IS A DIAGNOSIS OF EXCLUSION. LEFT VENTRICLE MAY NOT BE DILATED LVEF IS ALWAYS REDUCED BELOW 45% EXCLUDES CARDIAC DYSFUNCTION EARLY IN PREGNANCY INITIALLY DESCRIBED IN 1849 Richie, C.. Edinb Med Surg J 1849; 2:333 NOT RECOGNIZED AS A DISTINCT CLINICAL ENTITY UNTIL 1930 Hull E. New Orleans Med Surg J 1937; 89: DEMAKIS NAMED IT AS PERIPARTUM CARDIOMYOPATHY SYNONYMS: PREGNANCY-ASSOCIATED CMP; TOXIC POSTPARTUM HF; MEADOWS SYNDROME ; ZARIA SYNDROME; POSTPARTUM MYOCARDIOSIS

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: WCC&IVUS2015 EPIDEMIOLOGY WIDE GEOGRAPHICAL VARIATION UNITED STATES 1:2289 TO 1:4000 LIVE BIRTHS SOUTH AFRICA 1:1000 HAITI 1:300 NIGERIA 1:100 INDIA?? one case per 1374 live births AFRICAN AMERICANS - A HIGHER PREVALENCE AND MORE SEVERE DISEASE TEMPORAL TRENDS IN INCIDENCE AND OUTCOMES OF PERIPARTUM CARDIOMYOPATHY IN THE UNITED STATES: A NATIONWIDE POPULATION-BASED STUDY, 2014 TRENDS

5 PRESENTATION RARE BEFORE 36 WEEKS OF GESTATION & after 6 months POST-PARTUM 60% present within the first 2 months postpartum Up to 7% may present in the last trimester of pregnancy SYMPTOMS AND SIGNS VARIABLE AND SIMILAR TO THAT IN OTHER FORMS OF SYSTOLIC HF DUE TO CARDIOMYOPATHY MORE PRONE FOR THROMBOTIC EPISODES

6 DIAGNOSIS- NIH WORK GROUP JAMA 2000;283: THREE CLINICAL CRITERIA DEVELOPMENT OF HEART FAILURE (HF) TOWARD THE END OF PREGNANCY OR IN THE MONTHS FOLLOWING DELIVERY?? 5 MONTHS ABSENCE OF ANOTHER IDENTIFIABLE CAUSE OF HF THE ABSENCE OF RECOGNIZABLE HEART DISEASE PRIOR TO THE LAST MONTH OF PREGNANCY ONE ECHO CRITERIA LVEF <45 PERCENT/ FS < 30% / LVEDD >2.7CM/M SQUARE OF BODY SURFACE AREA2

7 RISK FACTORS WCC&IVUS2015

8 DIFFERENTIAL DIAGNOSIS ACCELERATED HYPERTENSION DIASTOLIC DYSFUNCTION SYSTEMIC INFECTION PREECLAMPSIA AMNIOTIC FLUID EMBOLUS MYOCARDIAL INFARCTION [CORONARY ARTERY DISSECTION, CORONARY ARTERY DISEASE, CORONARY EMBOLUS/THROMBOSIS AND CORONARY ARTERY SPASM PULMONARY EMBOLUS MITRAL STENOSIS/ OTHER SIGNIFICANT VALVULAR DISEASE, CONGENITAL HEART DISEASE

9 INVESTIGATIONS ECG is MOSTLT NON-SPECIFIC CXR- CE ECHO- GLOBAL HYPOKINESIA : LVE +/- ; MR +/- LAE/ LV clot BNP CARDIAC CATH- NOT NECESSARY EM BIOPSY RARELY CARDIAC MRI NOT USUALLY DONE

10 CARDIAC MAGNETIC RESONANCE IMAGING CAN BE HELPFUL TO ASSESS LV SYSTOLIC FUNCTION AND LV VOLUMES LATE GADOLINIUM ENHANCEMENT (LGE): THE PRESENCE AND PERSISTENCE- POOR RECOVERY OF CARDIAC FUNCTION IMPROVING LGE -good CARDIAC RECOVERY PROGNOSTIC VALUE OF CMR IN PPCM HAS NOT BEEN ESTABLISHED.

11 TREATMENT MOSTLY LIKE DCMP DIURETICS VASODILATORS INOTROPES DIGOXIN NO ACEI/ARB/ALD.ANTA? BETA-BLOCKERS ANTICOAGULATION ANTI-ARRHYTHMICS NO IMMUNOSUPPRESSIVE RX? IMMUNOGLOBULINS? BROMOCRIPTINE? CABERGOLINE IMMUNOADSORPTION PLASMAPHERESIS MECH.SUPPORT VENTRICULAR ASST.DEVICES ICD/CRT/CRT-D CARDIAC TRANSPLANTATION

12 DELIVERY-BREAST FEEDING URGENT DELIVERY MAY BE REQUIRED IF ADVANCED HF WITH HEMODYNAMIC INSTABILITY PLANNED CESAREAN DELIVERY IS PREFERRED BREAST FEEDING CONTROVERSIAL- PROBABLY GOOD TO CONTINUE

13 MORTALITY-TRANSPLANTATION RATES MORTALITY- 6 TO 10% (PROGRESSIVE PUMP FAILURE ; SUDDEN DEATH; THROMBOEMBOLIC EVENTS) TRANSPLANTATION RATES -4 TO 7 %

14 FOLLOW-UP IN THE STUDY OF 123 PATIENTS, DEGREE OF RECOVERY WAS GREATEST IN THOSE WITH A BASELINE LVEF >30 PERCENT. AN ICD OR PERMANENT PACEMAKER WAS REQUIRED IN 3 AND 2 PERCENT OF PATIENTS, RESPECTIVELY. ALMOST ALL OF THE RECOVERY OF LV FUNCTION OCCURRED BY SIX MONTHS AFTER DIAGNOSIS

15 PROGNOSIS 50-60% PATIENTS SHOW COMPLETE OR NEAR COMPLETE RECOVERY WITHIN THE FIRST 6 MONTHS POSTPARTUM OTHERS, EITHER CONTINUED CLINICAL DETERIORATION LEADING TO EARLY DEATH OR PERSISTENT LV DYSFUNCTION AND CHRONIC HEART FAILURE INITIAL HIGH RISK PERIOD WITH MORTALITY OF 25-50% IN THE FIRST 3 MONTHS POSTPARTUM PATIENTS WITH PERSISTENT CARDIOMEGALY AT 6 MONTHS HAVE A REPORTED MORTALITY OF 85% AT 5 YEARS.

16 Copyright American Heart Association, Inc. All rights reserved. WCC&IVUS2015 LONG TERM SURVIVAL IN PATIENTS WITH CARDIOMYOPATHY. Michael M. Givertz Circulation. 2013;127:e622-e626

17 PREDICTORS OF PERSISTENT LV DYSFUNCTION LVEF 30 PERCENT AN LV END-DIASTOLIC DIMENSION 6 CM ELEVATED CARDIAC TROPONIN T BLACK RACE

18 SUBSEQUENT PREGNANCY WITH PERSISTENT LV DYSFUNCTION OR LVEF 25 PERCENT AT DIAGNOSIS SHOULD BE ADVISED TO AVOID A SUBSEQUENT PREGNANCY DUE TO THE RISK OF HF PROGRESSION AND DEATH OTHER PATIENTS WITH PPCM SHOULD ALSO BE ADVISED OF THE RISK OF RECURRENCE [ 20% RELAPSE] TERMINATION OF PREGNANCY MAY NOT PREVENT RELAPSE.

19 RECENT INSIGHTS INTO ETIOPATHOGENESIS WCC&IVUS2015

20 MULTIFACTORIAL?? Not yet fully understood EXAGGERRATED REMODELLING RESPONSE NUTRITIONAL INFECTION INFLAMMATION ABNORMAL IMMUNE RESPONSE DEFECTIVE PROLACTIN PROCESSING/ EXCESS RELEASE EXCESS VEGF INHIBITOR PRODUCTION VASCULAR DAMAGE GENETIC SUSCEPTIBILITY

21 REVIEW ARTICL E published: 15 January JANUARY 2015 doi: /fphys Peripartum cardiomyopathy and dilated cardiomyopathy: different at heart Ilse A. E. Bollen, Elza D. Van Deel, Diederik W. D. Kuster and Jolanda Van Der Velden* Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, Netherlands

22 EXAGGERATED LV REMODELING RESPONSE

23 EXAGGERATED REMODELING RESPONSE DURING PREGNANCY, 40 TO 50 PERCENT INCREASE IN BLOOD VOLUME AND CARDIAC OUTPUT, TRANSIENT LV REMODELING AND HYPERTROPHY VEGF A- FACILITATES MYOCARDIAL ANGIOGENESS

24 EXAGGERATED REMODELING RESPONSE AN EXAGGERATED REMODELING RESPONSE [ PATHOLOGICAL ECCENTRIC HYPERTROPHY] WITH DECREASE IN LEFT VENTRICULAR SYSTOLIC FUNCTION THE HEMODYNAMIC STRESS OF GESTATIONAL HTN MAY CONTRIBUTE PHYSIOLOGICAL LVH: NO FIBROSIS NO FOETAL PROGRAM NORMALISES BY 1 YEAR

25 GENETIC PREDISPOSITION WCC&IVUS2015

26 GENETIC BASIS A STUDY OF 520 PEDIGREES IN THE FAMILIAL DCM RESEARCH PROJECT DATABASE FOUND 45 CASES OF PPCM AMONG 4110 WOMEN EVIDENCE OF FAMILIAL CLUSTERING OF DILATED CARDIOMYOPATHY WAS NOTED IN 23 OF 42 UNRELATED CASES KNOWN DCM MUTATIONS WERE FOUND IN FIVE CASES OF PPCM A STUDY EXAMINED 18 FAMILIES WITH PPCM AND DCM MUTATIONS IN 48 GENES KNOWN TO BE INVOLVED IN INHERITED CARDIOMYOPATHIES WERE EXAMINED. FOUR OF THE 18 FAMILIES HAD KNOWN PATHOGENIC MUTATIONS, WHILE SIX OTHER FAMILIES HAD VARIANTS THAT MAY BE PATHOGENIC WCC&IVUS2015

27 FAMILIAL OCCURRENCE? Familial disease is not well understood A STUDY AT THE UNIVERSITY CARDIO-GENETICS CLINIC - PPCM OCCURRED IN 5 (6 PERCENT) OF 90 FAMILIES WITH DCM SCREENING OF THE FIRST-DEGREE RELATIVES OF THREE PATIENTS WITH PPCM WHO DID NOT SHOW A FULL RECOVERY AT ONE YEAR FOUND UNDIAGNOSED DCM IN THE RELATIVES OF ALL THREE PATIENTS.

28 TITIN VARIANTS Titin (connectin) a protien, is responsible for the passive elasticity of muscle WCC&IVUS2015 LITTLE IS KNOWN ABOUT CULPRIT MUTATIONS SOME OVERLAP IN ETIOLOGY OF DCM AND PPCM TWO ISOFORMS- N2BA AND N2B IN DCM AND PPCM- MORE OF N2BA ISOFORM--- REDUCED PASSIVE STIFFNESS TITIN MUTATIONS MAY ACT AS DISEASE MODIFIERS? POTENTIAL FOR EARLY DIAGNOSIS

29 OXIDATIVE STRESS AND EXCESS PROLACTIN WCC&IVUS2015

30 reactive oxygen species WCC&IVUS2015

31 PROLACTIN WCC&IVUS2015

32 ROLE OF PROLACTIN & STAT3 cathepsin D-mediated cleavage of prolactin into its 16-kDa subform, Signal transduction and activator of transcription 3 (STAT3) WCC&IVUS2015

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34 Signal transduction and activator of transcription 3 (STAT3) a transcription factor- encoded by the STAT3 gene. WCC&IVUS2015

35 STAT3 LEVELS REDUCED CARDIAC STAT3 LEVELS HAVE BEEN OBSERVED IN TERMINALLY FAILING HEARTS FROM PPCM PATIENTS?? WHETHER STAT3 LEVELS ARE REDUCED IN PPCM AT AN EARLIER STAGE OF DISEASE.

36 VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) WCC&IVUS2015

37 VEGF- PRO-ANGIOGENIC WCC&IVUS2015

38 Soluble FLT1 SOLUBLE FLT1, A RECENTLY IDENTIFIED ENZYME IN THE TYROSINE KINASE FAMILY, APPEARS TO BE ANTI-ANGIOGENIC, CARDIOTOXIC AND PARTICULARLY ELEVATED IN BOTH PPCM AND PREECLAMPSIA

39 Role of SFLT1 SOLUBLE FMS-LIKE TYROSINE KINASE (SFLT1), WHICH DAMAGES THE VASCULATURE, WITH HIGHER LEVELS SEEN WITH MULTIPLE GESTATION OR PREECLAMPSIA AMONG WOMEN WITH PREECLAMPSIA, SUBCLINICAL CARDIAC DYSFUNCTION CORRELATES WITH SFLT1 LEVELS. DUAL PRO-ANGIOGENIC THERAPY (VEGF PLUS BROMOCRIPTINE)

40 ROLE OF MICRO RNA a small non-coding RNA molecule functions in RNA silencing and post-transcriptional regulation of gene expression

41 ROLE OF micro-rna THE 16 KDA PROLACTIN FRAGMENT (16K PRL) CAUSES ENDOTHELIAL DAMAGE AND MYOCARDIAL DYSFUNCTION THROUGH micro RNA-146A EXPRESSION WOMEN WITH PPCM HAVE ELEVATED LEVELS OF microrna- 146A COMPARED TO HEALTHY POSTPARTUM WOMEN OR WOMEN WITH OTHER CARDIOMYOPATHIES PHARMACOLOGICAL INHIBITION OF microrna 146A ATTENUATED PPCM IN STAT3 KNOCK-OUT MICE

42 ABNORMAL IMMUNE RESPONSE? Chimerism AUTOIMMUNE DISORDERS SUCH AS MULTIPLE SCLEROSIS WHICH AFFECT WOMEN DURING THEIR REPRODUCTIVE YEARS TYPICALLY HAVE LOWER RELAPSE RATES DURING PREGNANCY & MARKED INCREASE IN THE IMMEDIATE POSTPARTUM PERIOD FETAL CELLS MAY ESCAPE INTO THE MATERNAL CIRCULATION AND REMAIN THERE WITHOUT BEING REJECTED DUE TO WEAK IMMUNOGENICITY OF THE PATERNAL HAPLOTYPE OF THE CHIMERIC CELLS IF THESE CELLS LODGE IN THE CARDIAC TISSUE, THEY CAN TRIGGER A PATHOLOGIC AUTOIMMUNE RESPONSE HIGH TITERS OF AUTOANTIBODIES COMPARED TO CONTROLS AGAINST NORMAL HUMAN CARDIAC TISSUE PROTEINS

43 CELLULAR IMMUNITY AN INCREASE IN THE ACTIVATION OF REGULATORY T-CELLS AND INNATE IMMUNITY IS A NECESSARY PART OF ALL PREGNANCIES AN INCREASE OF T CELLS (CD3+ CD4- CD8- CD38) IN PPCM PATIENTS COMPARED TO HEALTHY POSTPARTUM PATIENTS NATURAL KILLER (NK) CELLS (CD3- CD56+ CD16+) ARE SIGNIFICANTLY REDUCED IN PPCM PATIENTS COMPARED TO HEALTHY POSTPARTUM WOMEN

44 IS IT MYOCARDITIS RELATED? EM BIOPSY MYOCARDITIS- 9 TO 78% A STUDY IN 2005 FOUND THAT 8 OF 26 PATIENTS HAD PARVOVIRUS B19, HUMAN HERPES VIRUS 6, EPSTEIN-BARR VIRUS, AND HUMAN CYTOMEGALOVIRUS DETECTED AFTER MOLECULAR ANALYSIS OF MYOCARDIAL BIOPSY SPECIMENS ABNORMAL MYOCARDIAL BIOPSY = A WORSE LONG-TERM PROGNOSIS FOR RECOVERY

45 INFLAMMATION & APOPTOSIS INCREASED LEVELS OF CATHEPSIN D, OXIDIZED LOW-DENSITY LIPOPROTEIN TNF-ALPHA INTERLEUKIN-6 FAS/APO-1 C-RP- INFLAMMATION AND APOPTOSIS OF CARDIAC MYOCYTES HAVE A ROLE IN PERIPARTUM CMP

46 INDIAN STUDY THE INFLAMMATORY MARKERS- SERUM HSCRP, TUMOR NECROSIS FACTOR-Α, AND INTERLEUKIN- HELPED TO PREDICT OUTCOME. Sarojini A, Sai Ravi Shanker A, Anitha M. Inflammatory Markers-Serum Level of C-Reactive Protein, Tumor Necrotic Factor-α, and Interleukin-6 as Predictors of Outcome for Peripartum Cardiomyopathy. J Obstet Gynaecol India 2013; 63:

47 NUTRITIONAL DISORDER MANY NUTRITIONAL FACTORSS HAVE BEEN SUGGESTED BUT OTHER THAN SALT OVERLOAD, NONE HAS BEEN VALIDATED MAY BE RELATED TO A LOCAL HAUSA CUSTOM OF EATING KANWA, A DRY LAKE SALT FOR FORTY DAYS AFTER DELIVERY? ZINC/ SELENIUM DEFICIENCY

48 COMMON FINAL PATHWAY WCC&IVUS2015

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50 ROLE OF BROMOCRIPTINE WCC&IVUS2015

51 USE OF BROMOCRIPTINE H. Yamac, I. Bultmann, K. Sliwa, and D. Hilfiker-Kleiner, Prolactin: a new therapeutic target in peripartum cardiomyopathy, Heart, vol. 96, no. 17, pp , B. G. Jahns, W. Stein, D. Hilfiker-Kleiner, B. Pieske, and G.Emons, Peripartum cardiomyopathy-a new treatment option by inhibition of prolactin secretion, American Journal of Obstetrics and Gynecology, vol. 199, no. 4, pp. e5 e6, D. Habedank, Y. K uhnle, T. Elgeti, J. W. Dudenhausen, W. Haverkamp, and R. Dietz, Recovery from peripartum cardiomyopathy after treatment with bromocriptine, European Journal of Heart Failure, vol. 10, no. 11, pp , 2008.

52 Bromocriptine Sliwa K Circulation 2010; 121:1465

53 BROMOCRIPTINE DATA ARE INSUFFICIENT TO RECOMMEND ROUTINE USE OF BROMOCRIPTINE TREATMENT FOR PPCM SAFETY IS QUESTIONED IN A FEW CASES RECENTLY REPORTED THE DRUG STOPS THE PRODUCTION OF BREAST MILK MAKING BREASTFEEDING IMPOSSIBLE

54 CABERGOLINE CABERGOLINE IS A STRONG AND LONG LASTING ANTAGONIST OF PROLACTIN SIGNIFICANT IMPROVEMENT IN LEFT VENTRICULAR FUNCTIONS WERE REPORTED [de Jong JS, Rietveld K, van Lochem LT et al; Rapid left ventricular recovery after cabergoline treatment in a patient with peripartum cardiomyopathy. Eur J Heart Fail 2009;11:220-2]

55 RECENT TRIALS Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D,Roentgen P, Tsikas D, Jordan J, Lichtinghagen R, von Kaisenberg CS, Struman I, Bovy N, Sliwa K, Bauersachs J, Hilfiker-Kleiner D. Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. Basic Res Cardiol 2013; 108: 366- BROMOCRIPTINE IS USEFUL Fett JD, Sanon H, Carraway RD, Markham DW, Ernst S. Pentoxifylline treatment for peripartum cardiomyopathy? J Cardiac Fail 2013; 19: S65-S66 [Pentoxifylline, as an inhibitor of the proinflammatory cytokine, Tumor Necrosis Factor-α]

56 SUMMARY AND RECOMMENDATIONS EXACT ETIOPATHOGENESIS IS STILL TO BE UNDERSTOOD TREATMENT IS LARGELY SUPPORTIVE; PREMATURE TO TELL IF NEW MODALITIES IMPROVED THE PROGNOSIS EARLY DIAGNOSIS WILL HELP A LOT;? NEW BIOMARKERS? REGISTERIES &LARGE STUDIES HAVE TO BE CONDUCTED ALL WOMEN WITH PPCM SHOULD RECEIVE COUNSELING ON THE POTENTIAL RISK OF RECURRENCE WITH FUTURE PREGNANCIES

57 THANK YOU ALL WCC&IVUS2015