PERI-PARTUM CARDIOMYOPATHY
Transcript of PERI-PARTUM CARDIOMYOPATHY
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PERI-PARTUM CARDIOMYOPATHY:Recent insights in its patho-physiology and treatment
DR.AN PATNAIK
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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, thickened, 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
[Heart Failure Association of the European Society of Cardiology Working Group on PPCM 2010]
Eur J Heart Fail. Aug 2010;12(8):767-78
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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; 89:550
• 1971-DEMAKIS – NAMED IT AS PERIPARTUM CARDIOMYOPATHY
SYNONYMS:
• PREGNANCY-ASSOCIATED CMP; TOXIC POSTPARTUM HF; MEADOWS’ SYNDROME ; ZARIA SYNDROME; POSTPARTUM MYOCARDIOSIS
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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
Pandit V, Shetty S, Kumar A et al; Incidence and out come of peripartumCardiomyopathy from a tertiary hospital in South India. Trop Doct 2009;39:168-9.WCC&IVUS2015
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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
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DIAGNOSIS- NIH WORK GROUPJAMA 2000;283:1183-88
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
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RISK FACTORS
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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
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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
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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.
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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
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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
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MORTALITY-TRANSPLANTATION RATES
• MORTALITY- 6 TO 10%
(PROGRESSIVE PUMP FAILURE ; SUDDEN DEATH; THROMBOEMBOLIC EVENTS)
• TRANSPLANTATION RATES -4 TO 7 %
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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
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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.
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LONG TERM SURVIVAL IN PATIENTS WITH CARDIOMYOPATHY.
Michael M. Givertz Circulation. 2013;127:e622-e626
Copyright © American Heart Association, Inc. All rights reserved.WCC&IVUS2015
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PREDICTORS OF PERSISTENT LV DYSFUNCTION
• LVEF ≤30 PERCENT
• AN LV END-DIASTOLIC DIMENSION ≥6 CM
• ELEVATED CARDIAC TROPONIN T
• BLACK RACE
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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.
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RECENT INSIGHTS INTO ETIOPATHOGENESIS
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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
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EREVIEW ARTICL
5published: 15 January 201
doi: 10.3389/fphys.2014.0053 1
Peripartum cardiomyopathy and dilated cardiomyopathy: different at heartIlse 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
JANUARY 2015
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EXAGGERATEDLV REMODELING RESPONSE
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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
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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
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GENETIC PREDISPOSITION
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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
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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.
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TITIN VARIANTSTitin (connectin) a protien, is responsible for the passive elasticity of muscle
• 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
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OXIDATIVE STRESS AND EXCESS PROLACTIN
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PROLACTIN
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ROLE OF PROLACTIN & STAT3cathepsin D-mediated cleavage of prolactin into its 16-kDa subform,
Signal transduction and activator of transcription 3 (STAT3) WCC&IVUS2015
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Signal transduction and activator of transcription 3 (STAT3) a transcription factor- encoded by the STAT3 gene.
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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.
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VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
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VEGF- PRO-ANGIOGENIC
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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
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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)
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ROLE OF MICRO RNA
a small non-coding RNA molecule functions in RNA silencing and post-transcriptional regulation of gene expression
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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
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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
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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
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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
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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
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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 PeripartumCardiomyopathy. J Obstet Gynaecol India 2013; 63:234-239
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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
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COMMON FINAL PATHWAY
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ROLE OF BROMOCRIPTINE
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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. 1352–1357, 2010.
• 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, 2008.
• 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. 1149–1151, 2008.
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BromocriptineSliwa K Circulation 2010; 121:1465
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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
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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 peripartumcardiomyopathy. Eur J Heart Fail 2009;11:220-2]
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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. Pentoxifyllinetreatment for peripartum cardiomyopathy? J Cardiac Fail 2013; 19: S65-S66
[Pentoxifylline, as an inhibitor of the proinflammatory cytokine, Tumor Necrosis Factor-α]
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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
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THANK YOU ALL
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