1. … could their antioxidant and antiinflammatory components interfere with prostaglandin metabolism and thus influence fetal ductus arteriosus dynamics? … could their antioxidant and antiinflammatory components interfere with prostaglandin metabolism and thus influence fetal ductus arteriosus dynamics?

2. ORIENTATION TO WITHDRAWL FOODS WITH MORE OF 30mg/100g COMPLETE REVERSION IN 96.3% (48/52 FETUSES WITH DUCTAL CONSTRICTION) (3 WEEKS AFTER SUSPENSION OF THE SUBSTANCES) FOOD FREQUENCY QUESTIONNAIRE FOR QUANTIFICATION OF DAILY INGESTION OF POLIPHENOLS

3. PREPOST 1.70 ± 0.41 2.19 ± 0.43 P=0.001 Pulsatility Index CONSTRICTION OF DUCTUS ARTERIOSUS

4. Polyphenols FLAVONOLS FLAVONS FLAVONONS FLAVAN - 3 - ONS ANTOCYANIDINS FLAVONOIDS CatequinasEpicatequinasTeaflavinas

5. ANTIINFLAMMATORY AND ANTIOXIDANT EFFECTS OF COMMON FOODS GREEN TEA BLACK TEA MATE TEA ORANGE JUICE DARK CHOCOLATE RESVERATROL

6. HERBAL TEAS AND OTHER FLAVONOID-RICH FOODS HERBAL TEAS AND OTHER FLAVONOID-RICH FOODS [3-gallate-gallocatechin, quercitin, cacao,…] [3-gallate-gallocatechin, quercitin, cacao,…] GRAPE DERIVATIVES GRAPE DERIVATIVES [resveratrol] POLYPHENOLS WITH ANTIINFLAMMATORY ACTIONS DEPENDENT ON INHIBITION OF COX-2 AND PROSTAGLANDINS FETAL DUCTAL CONSTRICTION ? 3rd TRIMESTER MATERNAL INGESTION

7. CONSTRICTION OF DUCTUS ARTERIOSUS

8. IN NORMAL FETUSES, DUCTAL FLOW DYNAMICS AND RIGHT VENTRICULAR SIZE ARE INFLUENCED BY MATERNAL CONSUMPTION OF POLYPHENOL-RICH FOODS (CASE-CONTROL STUDY)

9. Warn mothers about this... zielinsky@cardiol.br

10. 1509.05 mg/day (>perc 75) Daily consumption of polyphenols 0 1000 2000 AT DIAGNOSIS 80.05 mg/day (<perc 25) P= 0.0001 AFTER ORIENTATION GA=32 ± 2 wks (28 - 38 wks) CONSTRICTION OF DUCTUS ARTERIOSUS

11. SYST VEL DIASTVEL DIAST VEL PI DOPPLER BEFORE AND AFTER INGESTION OF GREEN TEA INGESTION OF GREEN TEA(CASES) p < 0.001 p =0.003 p < 0.001

12. VE VD Heart specimen of a fetal lamb exposed to green tea RV HYPERTROPHIC AND DILATED RV/LV RATIO

13. DUCTAL HISTOLOGY IN FETAL LAMB EXPOSED TO GREEN TEA DECREASED DUCTAL LUMEN AND INCREASED MEDIAL AVASCULAR ZONE THICKNESS DUCTAL LUMEN 687.7 um

14. 238.4 933.3 AVASCULAR ZONE Control AVASCULAR ZONE Case DUCTAL HISTOLOGY 746.6 ± 214.6 255.3 ± 97.9 p < 0.001 MEAN CONTROLS THICKNESS: MEAN CASES THICKNESS:

15. OBJECTIVE To investigate the interrelationships between fetal ductal flow dynamics, oxidative damage and polyphenol excretion after experimental exposure of PRF in sheep during late pregnancy 15

16. BASAL 14 DAYS ControlPRF Control PRF N=5 N=10 N= 2 N= 7 Statistics: Generalized Estimating Equations, post hoc Bonferroni. SUFFOLK SHEEP (90-100kg) >120 DAYS GESTATION STUDY SETUP Habitual diet (basic polyphenol ingestion) PRF supplementation (basic ingestion + 3100 mg/day

17. OPEN CLINICAL TRIAL 2 weeks 1st ECHO SUSPENSION OF POLYPHENOL_ RICH FOODS Nutritional Questionnaire 2nd ECHO3rd ECHO 2 weeks n = 72 FETUSES GA > 28 WEEKS

18. 1509.05 mg/day (>perc 75) Daily consumption of polyphenols 0 1000 2000 AT DIAGNOSIS 80.05 mg/day (<perc 25) P= 0.0001 AFTER ORIENTATION GA=32 ± 2 wks (28 - 38 wks) CONSTRICTION OF DUCTUS ARTERIOSUS

19. CONCLUSION OF INTERVENTIONAL STUDY The oriented restriction of maternal ingestion of polyphenol-rich foods in the third trimester is followed by regression of fetal ductal constriction. CONSTRICTION OF DUCTUS ARTERIOSUS

20. IN NORMAL FETUSES, DUCTAL FLOW DYNAMICS AND RIGHT VENTRICULAR SIZE ARE INFLUENCED BY MATERNAL CONSUMPTION OF POLYPHENOL-RICH FOODS (CASE-CONTROL STUDY)

21. 143 NORMAL FETUSES FROM NORMAL MOTHERS IN THE THIRD SEMESTER OF PREGNANCY 102 FETUSES WITH MATERNAL INGESTION OF POLIPHENOLS (> 75th PERCENTILE, 1089 MG) 1089 MG) 41 FETUSES WITHOUT MATERNAL INGESTION OF POLIPHENOLS (< 25th PERCENTILE, 127 MG) 28.4 ± 3.1 wks (23-38 wks) FETAL DOPPLER ECHOCARDIOGRAM

22. >PERC 75 <PERC 25 PERC 75 SYST VEL DIAST VEL RV/LV RATIO P<0.001 P=0.011 P<0.001 FETAL DUCTAL FLOW VELOCITIES AND RV/LV RATIO ACCORDING TO MATERNAL POLYPHENOL CONSUMPTION 0.96 0.96 0.17 1.23 0.61 0.11 0.94 >PERC 75 <PERC 25 >PERC 75 <PERC 25

23. Fetal ductal constriction detection in fetal CHD Consider the possibility of mild ductal constriction in any fetal left heart disease (HLHS) with a decreasing CV Profile score (TR, decreasing RV function) Counsel mothers on polyphenol foods early after fetal diagnosis

24. Use of Maternal Indomethacin and Fetal Ductal Constriction Indomethacin doses of 25 mg PO BID or TID are effective for tocolysis Short course of 48 hours is well tolerated Some types of ductal dependent CHD can have short-course indomethacin tocolysis safely i.e. pulmonary atresia, Tetralogy of Fallot, etc.

25. Effects of Indomethacin ductal closure in R heart disease e.g. Ebstein and TV dysplasia Constriction/occlusion of the ductus arteriosus Theoretical constriction of coronary arteries Increase in pulmonary vascular resistance Benefits Prevent or reverse pulmonary valve regurgitation Decrease tricuspid valve regurgitation Promote systolic pulmonary arterial flow Improve systemic flow

26. Approach to the fetus with CHD and preterm labor Early identification Address the cause (i.e. infection, indocin for poly) Aggressive management of cervical incompetence, Redefine “viability” Screen for CHF Consider tocolysis early

28. Advances in Perinatal Cardiology 10th Course Advances in Perinatal Cardiology 10th Fun in the Sun Course Focus: Fetal Cardiac Treatment Arrhythmia Management See www.allkids.orgwww.allkids.org “Conferences ” Oct.23-26, 2014 St. Petersburg, FL