1. Rimodellamento Ventricolare e Conversione del Rimodellamento: soni processi confrontabili nei due sessi? Marisa Di Donato IRCCS San Donato Hospital University of Florence Tenth International Symposium HEART FAILURE & Co. CARDIOLOGY SCIENCE UPDATE FEMALE DOCTORS SPEAKING ON FEMALE DISEASES Milano 9 - 10 aprile 2010

2. Sex impact on remodeling Aging cardiomyopathy WomenMen Preservation of cardiac weight Reduction in cardiac weight(1g/yr) Preseravtion of myocytes numberReduction in myocytes number (64 millions /yr) Preservation of myocytes volumeIncrease in myocytes volume Constant mononucleate/binucleate myocytes ratio Decreased mononucleate/binucleate myocytes ratio Low apoptotic indexApoptotic index 3-fold higher than women Decreased apoptotic rateIncreased apoptotic rate Piro et al. JACC 2010;55:1057

3. Aging cardiomyopathy The basis for the differential impact of aging on the heart is unknown A potential explanation may be related to the higher cardiac work load of male hearts throughout life Another explanation could be the higher rate of apoptosis in men

4. Sex impact on remodeling Response to Pressure Overload Women Earlier improvement in EF (after AVR) Greater degree of LVH Increased LV mass Increased RWT Smaller EDVI and ESVI Preserved LV function Later onset of pump dysfunction Higher expression of beta myosin heavy chain Higher expression of ANF mRNA Men Later improvement After AVR Lower degree of LVH Impaired LV function Earlier onset of pump dydfunction Lower expression of beta myosin heavy chain Lower expression of ANF mRNA Piro et al. JACC 2010;55:1057

5. Sex impact on remodeling Response to Volume Overload WomenMen Smaller EDV and ESVLarger EDV and ESV Greater LV mass/volume ratioLower LV mass/volume ratio Concentric hypertrophyNo concentric hypertrophy No impairment in cardiac functionImpairment in cardiac function Minimal ventricular dilatation No changes in myocardial compliance Significant ventricular dilatation Decreased ventricular compliance Piro et al. JACC 2010;55:1057

6. Sex impact on remodeling Response to acute myocardial ischemia WomenMen Lower apoptotic rate in peri-infarct zone10-fold higher apoptotic rate in peri-infarct zone Longer duration of the cardiomyopathy Later onset of cardiac decompensation Shorter duration of the cardiomyopathy Earlier onset of cardiac decompensation Longer interval between HF and Transplantation Lower infarct expansion index Shorter interval between HF and Transplantation Higher infarct expansion index Three times lower mortalityWorse cardiac function Better cardiac functionMaladaptive remodeling Better remodelingSignificantly greater dilatation Myocytes hypertrophy Premature exracellular matrix degradation Higher number of neutrophylis Increased activity of metalloproteinase Piro et al. JACC 2010;55:1057

7. Sex impact on remodeling Heart Failure WomenMen Preserved LV EFImpaired LV EF Smaller LV End diastolic volume Smaller Stroke Volume Higher LV end diastolic pressure More frequent congestive symptoms Greater LV End diastolic volume Greater Stroke Volume Lower LV end diastolic pressure Less frequent congestive symptoms Greater impairment in diastolic fillingLower impairment in diastolic filling

8. Sex impact on remodeling and the role of estrogens The mechanism by which estrogens exert their cardio-protective effects are not completely understood Ovarian synthesis of estrogens is subject to dramatic changes during the course of life but intramyocardial synthesis is less influenced by such variations (Grohe 1998)

9. Sex impact on remodeling and the role of estrogens Metabolic and vascular effects Endotelium-dependent flow-mediated dilatation and aortic compliance are greater in women Estrogens reduce cytopatic damage associated with myocardial injury (less apoptosis) Androgens adversely affect myocardial healing (Higher rate of rupture in men) and promote cardiac remodeling and dysfunction

10. Diastolic Heart Failure The reduced ventricular dilatation during remodeling in women compared with men helps explain why approximately half of women presenting with HF symptoms have preserved EF, vs one/third of men (Cleland JC, Eur Heart J 2003) When affected by HF women are more likely than men to present with congestive symptoms Both men and women with diastolic dysfunction and preserved EF show an increase in End diastolic pressure-volume ratio

11. THE PROCESS OF POST_INFARCTION REMODELING Gender & Heart Failure ● Myocardial Changes Myocyte loss Necrosis Apoptosis ● Alterations in extracellular matrix ● Matrix degradation ● Replacement fibrosis ● Alteration in LV chamber geometry ● LV dilation (SIZE) ● Increased LV sphericity (SHAPE) ● LV wall thinning (SHAPE) ● Mitral valve incompetence (SIZE AND SHAPE) IRCCS Policlinico San Donato

12. Sex Differeces after MI 0.02 0.001 0.05 496 pts (89 women) San Donato Hospital (unpublished)

13. Pattern of LV Remodeling after Myocardial Infarction In Women % Concentric Eccentric Dilatation 496 pts (89 women) San Donato Hospital (unpublished)

14. Pattern of LV Remodeling after Myocardial Infarction In Men Concentric Eccentric Dilatation 496 pts (89 women) San Donato Hospital (unpublished) %

15. EDVI(ml/m2) ESVI(ml/m2 ) Sex impact on LV Remodeling after Myocardial Infarction 0.001 496 pts (89 women) San Donato Hospital (unpublished)

16. Sex impact on LV Remodeling after Myocardial Infarction P 0.04 Relative wall Thickness 496 pts (89 women) San Donato Hospital (unpublished)

17. Sex impact on LV Remodeling after Myocardial Infarction LV Mass Index(g.m 2 ) Left Atrium Size (mm) 0.006 0.003 496 pts (89 women) San Donato Hospital (unpublished)

18. Women Men 0.007 0.001 Sex impact on LV Shape after Myocardial Infarction (Median Values) SPHERICITYINDEXSPHERICITYINDEX Sphericity Index= Short to Long axis ratio San Donato Hospital (unpublished)

19. MI N Sex impact on LV Apical Shape (Conicity Index) after MI Diastole Systole MI N MI N 0.001 0.0001 0.01 Conicity Index (CI)= Apical to Short axis ratio San Donato Hospital (unpublished)

20. Sex impact on Global and Regional LV shape after MI L S A Sphericity Index= S/L Conicity Index= A/S SI= 0.46 CI=1.12 SI= 0.55 CI=0.78

21. Is it possible to revert LV remodeling? Is there a difference in women compared to men in reverting the remodeling process ?

22. Non pharmachologic approaches to revert/retard LV remodeling ● Cardiomyoplasty ● Volume reduction surgery (Batista operation) ● Mitral valve repair +/-CABG ●VAD implantation ● CRT ● LV reconstruction (Dor procedure) ● Mannequin guided surgical ventricular restoration (SVR- Menicanti) ● Prosthetic restraint devices ● Cells replacement

23. Surgical technique Arrested heart Use of intraventricular mannequin to re-size and re-shape Complete coronary revascularization Mitral repair through ventricular approach, if needed Cryosurgery at the border of the lesion if VA present San Donato Hospital, Milano Italy Menicanti 2002

24. San Donato Hospital Series Pts submitted to SVR (2001-2009) O496 Patients with previous MI: 89 Women (age 68+/-10 yrs)** 407 Men (age 64+/-9 yrs) O NYHA III-IV: Men 166/384 (43%) Women 50/83 (56%)** O CABG associated in 93% of women and 94% of men O Mitral repair in 25% of men and 27% of women O Operative mortality: Men27/408 (7.6%) Women 9/89 (10%) NS

25. ….SURGERY for LV remodeling Pre Post Pre

26. + Women Men Reverse remodeling at 12 months FUP induced by SVR

27. Long AxisShort Axis Apical Axis Reverse remodeling at 12 months FUP induced by SVR Long AxisShort Axis Apical Axis Women Men

28. Pre-op Post-op Pre-op Post-op Changes in Sphericity Index following SVR Diastole Systole 0.01

29. Sex impact following Surgical Ventricular Reconstruction for post-infarction LV remodeling

30. LVR can revert the remodeling process both in men and women, by reducing Ventricular size and improving apical shape A more physiologic apex is the key to re- direct the blood flow towards the aorta and improving cardiac function Prognosis following LVR is not impacted by sex Conclusions

31. Regardless of age and menopause the remodeling process appears to be more favourable in women Women are more likely to present with “diastolic only” dysfunction and are at greater risk for low output syndrome acutely Lower awareness of heart disease in women is likely responsible for the worse outcome observed in some clinical series, and since this issue can be corrected,increased awareness of heart disease among women should still represent a number one priority

32. THANKS